EP1490340A1 - Heteroaromatic urea derivatives as vr-1 receptor modulators for treating pain - Google Patents
Heteroaromatic urea derivatives as vr-1 receptor modulators for treating painInfo
- Publication number
- EP1490340A1 EP1490340A1 EP03710014A EP03710014A EP1490340A1 EP 1490340 A1 EP1490340 A1 EP 1490340A1 EP 03710014 A EP03710014 A EP 03710014A EP 03710014 A EP03710014 A EP 03710014A EP 1490340 A1 EP1490340 A1 EP 1490340A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- description
- mmol
- trifluoromethyl
- mixture
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 208000002193 Pain Diseases 0.000 title claims abstract description 28
- -1 Heteroaromatic urea derivatives Chemical class 0.000 title claims description 100
- 150000001875 compounds Chemical class 0.000 claims abstract description 228
- 238000000034 method Methods 0.000 claims abstract description 94
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 21
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 125000001424 substituent group Chemical group 0.000 claims abstract description 17
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 14
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 13
- 206010061218 Inflammation Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 230000004054 inflammatory process Effects 0.000 claims abstract description 9
- 125000004452 carbocyclyl group Chemical group 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical group 0.000 claims description 25
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 10
- 229940002612 prodrug Drugs 0.000 claims description 10
- 239000000651 prodrug Substances 0.000 claims description 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- 150000001721 carbon Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 239000005557 antagonist Substances 0.000 abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 299
- 239000000203 mixture Substances 0.000 description 218
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 217
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 204
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 131
- 235000013877 carbamide Nutrition 0.000 description 117
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 115
- 239000004202 carbamide Substances 0.000 description 111
- 239000000243 solution Substances 0.000 description 111
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 90
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 77
- 239000002253 acid Substances 0.000 description 74
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
- 238000006243 chemical reaction Methods 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- 235000019439 ethyl acetate Nutrition 0.000 description 49
- 239000007832 Na2SO4 Substances 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 43
- 238000007792 addition Methods 0.000 description 43
- 238000010992 reflux Methods 0.000 description 43
- 229910052938 sodium sulfate Inorganic materials 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 239000012044 organic layer Substances 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 30
- 238000004440 column chromatography Methods 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 29
- MBBQXHDBRSSIKS-UHFFFAOYSA-N 1-(isocyanatomethyl)-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(CN=C=O)C=C1 MBBQXHDBRSSIKS-UHFFFAOYSA-N 0.000 description 28
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 28
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- 239000012267 brine Substances 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- 239000010410 layer Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 22
- 239000003054 catalyst Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 235000011114 ammonium hydroxide Nutrition 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 239000000377 silicon dioxide Substances 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 19
- YUHZIUAREWNXJT-UHFFFAOYSA-N (2-fluoropyridin-3-yl)boronic acid Chemical class OB(O)C1=CC=CN=C1F YUHZIUAREWNXJT-UHFFFAOYSA-N 0.000 description 18
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 16
- 239000012948 isocyanate Substances 0.000 description 16
- 150000002513 isocyanates Chemical class 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 235000019198 oils Nutrition 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 14
- 229960002504 capsaicin Drugs 0.000 description 14
- 235000017663 capsaicin Nutrition 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 10
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000002002 slurry Substances 0.000 description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 9
- 239000011737 fluorine Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 238000010828 elution Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 150000002431 hydrogen Chemical group 0.000 description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 238000012746 preparative thin layer chromatography Methods 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- KUJMVQREQZBJPG-UHFFFAOYSA-N 1-(isocyanatomethyl)-4-(trifluoromethoxy)benzene Chemical compound FC(F)(F)OC1=CC=C(CN=C=O)C=C1 KUJMVQREQZBJPG-UHFFFAOYSA-N 0.000 description 7
- PJNILWKRAKKEQM-UHFFFAOYSA-N 2-bromo-6-fluorobenzaldehyde Chemical compound FC1=CC=CC(Br)=C1C=O PJNILWKRAKKEQM-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- AHKMQKHWBPNHAH-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methylurea Chemical compound NC(=O)NCC1=CC=C(C(F)(F)F)C=C1 AHKMQKHWBPNHAH-UHFFFAOYSA-N 0.000 description 7
- 239000000908 ammonium hydroxide Substances 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 230000008570 general process Effects 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 230000000630 rising effect Effects 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 125000001544 thienyl group Chemical group 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
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- 229940113118 carrageenan Drugs 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 210000002683 foot Anatomy 0.000 description 6
- 125000002541 furyl group Chemical group 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 125000001786 isothiazolyl group Chemical group 0.000 description 6
- 125000002971 oxazolyl group Chemical group 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 235000015320 potassium carbonate Nutrition 0.000 description 6
- 125000000168 pyrrolyl group Chemical group 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 125000001113 thiadiazolyl group Chemical group 0.000 description 6
- 150000003672 ureas Chemical class 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
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- 230000002378 acidificating effect Effects 0.000 description 5
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- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
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- ZIPLFLRGHZAXSJ-UHFFFAOYSA-N isoquinoline-5-carboxylic acid Chemical compound N1=CC=C2C(C(=O)O)=CC=CC2=C1 ZIPLFLRGHZAXSJ-UHFFFAOYSA-N 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 5
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- 208000004454 Hyperalgesia Diseases 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 4
- 235000019502 Orange oil Nutrition 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention is concerned with heteroaromatic ureas and 5 pharmaceutically acceptable salts and prodrugs thereof which are useful as therapeutic compounds, particularly in the treatment of pain and other conditions ameliorated by the modulation of the function of the vani loid-1 receptor (VR1).
- VR1 vani loid-1 receptor
- capsaicin recognised for some time to be the phenolic amide capsaicin.
- the beneficial effects of topical administration of capsaicin as an analgesic is also well established.
- understanding of the underlying molecular pharmacology mediating these responses to capsaicin has
- VE1 receptors are cation channels that are found on sensory nerves that innervate the skin, viscera, peripheral tissues and spinal cord. Activation of NRl elicits action
- NRl receptor is activated not only by capsaicin by also by acidic pH and by noxious heat stimuli and thus appears to be a polymodal integrator of painful stimuli.
- the prototypical NRl antagonist is capsazepine (Walpole et al,
- Iodo-resiniferatoxin (Wahl et al, Mol. Pharmacol, 59:9, 2001) is a nanomolar antagonist of NRl but does not possess properties suitable for an oral pharmaceutical. This last is also true of the micromolar peptoid antagonists described by Garcia-Martinez (Proc. Natl. Acad. Sci., USA, 99:2374, 2002). Most recently International (PCT) patent publication No. WO 02/08221 has described a novel series of NRl antagonists, which are stated to show efficacy in a number of animal models. We herein describe another novel series of NRl modulators. These comprise predominantly NRl antagonists but encompass NRl partial antagonists and NRl partial agonists. Such compounds have been shown to be efficacious in animal models of pain.
- Structurally related compounds are disclosed in EP-A-0418071, WO-A- 9104027, WO-A-9324458, US-A-5596001 and US-A-5362818 all in the name of Pfizer Inc., WO-A-0064888 and WO-A-0064876 in the name of Aventis Pharmaceutical Products Inc. and WO-A-9406280 in the name of The Regents of the University of California. None of the compounds disclosed are for treating pain.
- the present invention provides compounds of formula (I):
- A, B, D and E are each C or N with the proviso that one or more are N;
- R 1 and R 2 are each independently hydrogen, halogen, hydroxy, Ci- ⁇ alkyl, C2-6alkenyl, C2-6alkynyl, haloCi- ⁇ alkyl, hydroxyCi- ⁇ alkyl, Ci- ⁇ alkoxy, haloCi- ⁇ alkoxy, hydroxyCi- ⁇ alkoxy, C3-7cycloalkyl, C3-5cycloalkylC ⁇ - alkyl, NR 7 R 8 , carboxy, esterified carboxy, Ci- ⁇ alkyl substituted with a group selected from NR 7 R 8 , carboxy and esterified carboxy, or Ci- ⁇ alkoxy substituted with a group selected from NR 7 R 8 , carboxy and esterified carboxy;
- R 8 and R 4 are each independently hydrogen, Ci- ⁇ alkyl, C2-6alkenyl or C2-6alkynyl;
- R 5 and R 6 are, at each occurrence, independently hydrogen, Ci- ⁇ alkyl, C2-6alkenyl, C2-6alkynyl, Ci- ⁇ alkoxy, Ci- ⁇ acyloxy, carboxy, esterified carboxy, CONR 7 R 8 , SO2R 7 , SO2NR 7 R 8 , aryl, heteroaryl, heterocyclyl, or C ⁇ -6alkyl substituted with a group selected from hydroxy, Ci- ⁇ alkoxy, Ci- ⁇ acyloxy, carboxy, esterified carboxy, NR 7 R 8 , CONR 7 R 8 , SR 7 , SO2R 7 , SO 2 NR 7 R 8 , aryl, heteroaryl and heterocyclyl; or R 5 and R 6 and the carbon atom to which they are attached together form a carbocyclic ring of 3 to 6 carbon atoms
- R 7 and R 8 are, at each occurrence, independently hydrogen, Ci- ⁇ alkyl, C2-6alkenyl,
- Y is an aryl, heteroaryl, carbocyclyl or fused-carbocyclyl group; and n is either zero or an integer from 1 to 3; or a pharmaceutically acceptable salt, N-oxide or a prodrug thereof.
- R 1 may be absent or one or two R 1 groups may be present, as a preferred embodiment.
- R 1 is thus preferably chosen independently from halogen, haloCi- ⁇ alkyl and Ci-ealkoxy, such as fluorine, chlorine, trifluoromethyl and methoxy.
- a preferred class of compound of formula (I) is that wherein R 1 is a hydrogen or halogen atom or a group selected from Ci- ⁇ alkyl and Ci- ⁇ alkoxy. More particularly, a preferred class of compound of formula (I) is that wherein R 1 is a hydrogen or a halogen atom, particularly a hydrogen or a fluorine atom, and most especially a hydrogen atom.
- R 1 is other than hydrogen, preferably there is only one R 1 substituent.
- R 2 is absent or one or two R 2 groups are present.
- R 2 is preferably independently chosen from Ci- ⁇ alkoxy, halogen, di(C ⁇ -6alkyl)amino,
- R 2 is particularly chosen independently from methoxy, methyl, ethyl, chlorine, dimethylamino, hydroxy, trifluoromethyl, methoxycarbonyl, carboxy, amino, hydroxymethyl and aminoethyl.
- Another preferred class of compound of formula (I) is that wherein R 2 is a hydrogen or halogen atom or a group selected from Ci- ⁇ alkyl, haloCi-ealkyl, Ci-ealkoxy, NR 7 R 8 , Ci-ealkyl substituted with NR 7 R 8 , and Ci- ⁇ alkoxy substituted with NR 7 R 8 , wherein R 7 and R 8 each independently preferably represent hydrogen atoms or C ⁇ -4alkyl groups.
- a further preferred class of compound of formula (I) is that wherein R 2 is a hydrogen or a halogen atom, or a group selected from C ⁇ - 4 alkyl, C1.4aIk.oxy and NR 7 R 8 , wherein R 7 and R 8 each independently preferably represent hydrogen atoms or C ⁇ - 4 alkyl groups. More particularly, R 2 preferably represents a hydrogen or chlorine atom or a group selected from methyl, methoxy and dimethylamino. Most preferably, R 2 is a hydrogen atom.
- R 2 is other than hydrogen, preferably there is only one R 2 substituent.
- quinoline, isoquinoline and cinnoline moieties included within the scope of the invention include isoquinolin-5-yl, isoquinolin-8-yl, quinolin-5-yl, 2-oxidoisoquinolin-5-yl, 3-methoxyisoquinolin-8-yl, cinnolin-5-yl, 3- methylisoquinohn-5-yl, l-chloroisoquinolin-5-yl, l-dimethylaminoisoquinolin-5-yl, 3-methylisoquinoHn-8-yl, 3-chloroisoquinolin-5-yl, 3-methylcinnolin-5-yl, 8- fl.uoroisoquinolin-5-yl, l-hydroxyisoquinoHn-5-yl, 3-trifluoromethylisoquinolin-5- yl, l-chloro-3-eth
- a yet further preferred class of compound of formula (I) is that wherein R 4 is a hydrogen atom or a C ⁇ - 4 alkyl group, particularly a hydrogen atom or a methyl group, and most especially a hydrogen atom.
- R 5 and R 6 each independently represent a hydrogen atom or a group selected from Ci- ⁇ alkyl, C ⁇ -6alkyl substituted by a group selected from hydroxy, Ci- ⁇ acyloxy, carboxy, esterified carboxy, NR 7 R 8 and heterocyclyl, or an aryl group
- a preferred class of compound of formula (I) is that wherein R 5 and R 6 each independently represent a hydrogen atom or a C ⁇ -4alkyl or phenyl group, particularly a hydrogen atom or a methyl group, and most especially a hydrogen atom.
- R 5 and R 6 each independently represent a hydrogen atom or a C ⁇ -4alkyl or phenyl group, particularly a hydrogen atom or a methyl group, and most especially a hydrogen atom.
- -(CR 5 R 6 )n- can represent a bond, -CH2-, -(CEfeV, -(CH.2)3-,
- a further preferred class of compound of formula (I) is that wherein X is an oxygen atom. X may be sulphur or oxygen.
- a yet further preferred class of compound of formula (I) is that wherein Y is an aryl group selected from unsubstituted phenyl or naphthyl and phenyl or naphthyl substituted by one or two substituents selected from halogen, C ⁇ - 4 alkyl, C ⁇ -4alkoxy, haloC ⁇ .4alkyl, haloC ⁇ -4alkoxy, phenyl, cyano, nitro, pyrazolyl, di(C ⁇ -6alkyl)amino, phenoxy, -OCH2O- and Ci- ⁇ alkylcarbonyl; or a heteroaryl group selected from pyridyl, thiazolyl, isoxazolyl, oxadiazolyl and pyrazolyl wherein each heteroaryl group is optionally substituted with one or two substituents selected from C ⁇ -4alkyl, C ⁇ -4alkoxy, haloC ⁇ -4alkyl, haloC ⁇ -4alkoxy,
- a yet further preferred class of compound of formula (I) is that wherein Y is an aryl group selected from unsubstituted phenyl and phenyl substituted by one or two substituents selected from halogen, C ⁇ - 4 alkyl, C ⁇ .4a]koxy, haloC ⁇ -4alkyl, haloC ⁇ -4alkoxy, phenyl and pyrazolyl; or a heteroaryl group selected from pyridyl, thiazolyl, isoxazolyl, oxadiazolyl and pyrazolyl wherein each heteroaryl group is optionally substituted with one or two substituents selected from C ⁇ -4alkyl, C ⁇ -4alkoxy, haloC ⁇ .4alkyl, haloC ⁇ -4alkoxy, phenyl; or a carbocyclyl group which is a C5-7cycloalkyl radical that is unsubstituted or substituted by a phenyl ring; or a fused
- Y can be phenyl, biphen-4-yl, biphen-3-yl, l,2,3,4-tetrahydronaphthalen-2-yl, 4-chlorophenyl, 3,5-di(trifl.uoromethyl)phenyl, 3,4-dime hylphenyl, 4-tertbutylphenyl, 3-tertbutylphenyl, 3- trifluoromethylphenyl, 4-triQ.uoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 2, 3-dihydro- lH-inden-2-yl, 4-phenylcyclohexyl, 6, 7, 8, 9-tetrahydro-5H- benzo [a] [7] annulen-6-yl, 6, 7, 8, 9-tetrahydro-5H-benzo[a] [7] annulen- 7-yl, 3-trifLuoromethylpyridin-6-yl, 4-tertbutylpyridin-6-yl
- Another preferred class of compound of formula (I) is that wherein one of A, B, D and E is a nitrogen atom and the other three are carbon atoms, or A and B are nitrogen atoms and D and E are carbon atoms. It will be appreciated that the group R 2 is attached to any available carbon atom represented by A, B, D and E.
- R 7 is preferably a hydrogen atom or a C ⁇ -4alkyl group
- R 8 is preferably a hydrogen atom or a C ⁇ .4alkyl group
- the group NR 7 R 8 represents a heteroaliphatic ring selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorphohnyl, piperazinyl or a piperazinyl group substituted on the nitrogen atom by C ⁇ -4alkyl optionally substituted by hydroxy or C ⁇ - 4 alkoxy.
- the group NR 7 R 8 represents a group selected from -NH2- -NHCH3, -N(CH 3 ) 2 , -NHCH2CH3, -N(CH)CH 2 CH3 and -N(CH 2 CH 3 )2, and most especially, -N(CH-3)2.
- One favoured class of compound of the present invention is that of formula (la) and pharmaceutically acceptable salts, N-oxides and prodrugs thereof:
- E is a carbon atom.
- one of A, B and D is a nitrogen atom and the others are carbon atoms, or where A and B are nitrogen atoms and D and E are carbon atoms.
- Another favoured class of compound of the present invention is that of formula (lb) and pharmaceutically acceptable salts, N-oxides and prodrugs thereof:
- E is a carbon atom.
- E is a carbon atom.
- one of A, B and D is a nitrogen atom and the others are carbon atoms, or where A and B are nitrogen atoms and D and E are carbon atoms.
- A is a nitrogen atom and B, D and E are carbon atoms.
- alkyl or “alkoxy” as a group or part of a group means that the group is straight or branched.
- suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl.
- suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
- hydroxyCi-ealkyl means a Ci- ⁇ alkyl group in which one or more (in particular 1 to 3, and especially 1) hydrogen atoms have been replaced by hydroxy groups.
- Particularly preferred are hydroxyC ⁇ -3alkyl groups, for example, CH2OH, CH2CH2OH, CH(CH 3 )OH or C(CH 3 )2OH, and most especially CH2OH.
- haloCi- ⁇ alkyl and “haloCi- ⁇ alkoxy” means a Ci- ⁇ alkyl or Ci- ⁇ alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms.
- fluoroCi- ⁇ alkyl and fluoroCi- ⁇ alkoxy groups in particular, fl.uoroC ⁇ -3alkyl and fl.uoroC ⁇ -3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3. OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF 3 , OCF3 and OCH2CF3.
- cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- Suitable C3-7cycloalkylC ⁇ -4alkyl groups include, for example, cyclopropylmethyl and cyclohexylmethyl.
- cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
- alkenyl and “alkynyl” as a group or part of a group means that the group is straight or branched.
- suitable alkenyl groups include vinyl and allyl.
- a suitable alkynyl group is acetylene or propargyl.
- halogen means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
- carboxy as a group or part of a group denotes CO2H.
- esterified carboxy groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
- esterified carboxy groups include, for example, acetoxy, propionyloxy, isopropionyloxy and trifluoroacetoxy.
- aryl as a group or part of a group means an aromatic radical such as phenyl, biphenyl or naphthyl, wherein said phenyl, biphenyl or naphthyl group may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci- ⁇ alkyl, Ci- ⁇ alkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR 7 R 8 , benzyl, NO 2 , cyano, SR b , SOR , SO 2 R b , COR b , CO 2 R b , CONR R c , C2-6alkenyl, C ⁇ alkynyl, C ⁇ - 4 alkoxyC ⁇ -4alkyl, -O(CH2)mO- or a heteroaromatic group selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl,
- aryl as a group or part of a group means an aromatic radical such as phenyl, biphenyl or naphthyl, wherein said phenyl, biphenyl or naphthyl group may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci- ⁇ alkyl, Ci- ⁇ alkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR 7 R 8 , benzyl, NO 2 , cyano, SR , SOR b , SO 2 R b , COR b , CO 2 R b , CONR b R c , C 2 .
- phenyl, biphenyl or naphthyl group is optionally substituted by one or two substituents, especially none or one.
- substituents include fluorine, chlorine, C ⁇ -4alkyl (especially methyl or t-butyl), C ⁇ -4alkoxy (especially methoxy), trifluoromethyl or trifiuoromethoxy.
- heteroaryl as a group or part of a group means a 5 or 6-membered monocyclic heteroaromatic radical containing from 1 to 4 nitrogen atoms or an oxygen atom or a sulfur atom, or a combination thereof, or an 8- to 10-membered bicyclic heteroaromatic radical containing from 1 to 4 nitrogen atoms or an oxygen atom or a sulfur atom or a combination thereof.
- Suitable examples include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl and cinnolinyl, wherein said heteroaromatic radicals may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci- ⁇ alkyl, Ci- ⁇ alkoxy, haloCi-ealkyl,
- heteroaromatic radical is optionally substituted by one or two substituents, especially none or one.
- substituents include C ⁇ -4alkyl (especially methyl or tert-butyl), C ⁇ - 4 alkoxy (especially methoxy), trifluoromethyl, trifiuoromethoxy, phenyl, phenyl substituted by halogen (especially fluorine) and C ⁇ -4alkyl (especially methyl), benzyl, or thienyl.
- the term "carbocyclyl" as a group or part of a group means a 3 to 7-membered cycloalkyl radical such as cyclobutyl, cyclopentyl or cyclohexyl, wherein said cycloalkyl radical may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci- ⁇ alkyl, Ci-ealkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR 7 R 8 , phenyl, phenyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy, benzyl, NO2, cyano, NR b R c , SR b , SOR , SO 2 R b , COR , CO 2 R b , CONR R c , C 2 .
- fused-carbocyclyl as a group or part of a group means a 3 to 7-membered cycloalkyl radical such as cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, wherein said cycloalkyl radical is fused to an aryl or heteroaryl group as herein defined.
- said fused-carbocylyl group is attached to the remainder of the molecule via a carbon atom of the cycloalkyl radical.
- said cycloalkyl radical is fused to a phenyl or pyridyl ring where said phenyl ring is optionally substituted by a group selected from halogen (especially fluorine) and fl.uoroC ⁇ .4alkyl (especially trifluoromethyl), furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, and said pyridyl ring is optionally substituted by a group selected from halogen (especially fluorine) and fl.uoroC ⁇ .4alkyl (especially trifluoromethyl).
- said cycloalkyl radical is fused to a phenyl ring.
- Particular compounds of the invention include:
- N-isoquinoHn-6-yl-N-[4-(trifluoromethoxy)benzyl]urea 20 ⁇ (S-methyHsoquinohn- ⁇ -y ⁇ -N- ⁇ - ⁇ rifluoromethy ⁇ benzyllurea;
- the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
- the salts of the compounds of formula (I) will be 2 ⁇ non-toxic pharmaceutically acceptable salts.
- Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound 30 according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p -toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
- a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p -toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
- Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
- suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or ⁇ magnesium salts.
- the salts may be formed by conventional means, such as by reacting the free base form of the compound of formula (I) with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by 10 exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
- N-oxides of the compounds of formula (I) above include within its scope N-oxides of the compounds of formula (I) above.
- such N-oxides may be formed on any available nitrogen atom, and preferably on any one of A, B, D or E where they l ⁇ represent a nitrogen atom.
- the N-oxides may be formed by conventional means, such as reacting the compound of formula (I) with oxone in the presence of wet alumina.
- the present invention includes within its scope prodrugs of the compounds of formula (I) above.
- prodrugs will be functional derivatives of 20 the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I).
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 198 ⁇ .
- a prodrug may be a pharmacologically inactive derivative of a biologically 25 active substance (the "parent drug” or “parent molecule”) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecxile.
- the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or 30 reduction or oxidation of a susceptible functionality.
- the present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
- the compounds according to the invention may have one or more asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, the compounds of formula (I) may also exist in tautomeric forms and the invention includes within its scope both mixtures and separate individual tautomers.
- the present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
- compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices, suppositories, creams or gels; for oral, parenteral, intrathecal, intranasal, sublingual, rectal or topical administration, or for administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
- a pharmaceutical carrier e.g.
- pre-formulation compositions containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- Favoured unit dosage forms contain from 1 to 500 mg, for example 1, 5, 10, 2 ⁇ , ⁇ O, 100, 300 or ⁇ OO mg, of the active ingredient.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric ⁇ layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Suitable dispersing or l ⁇ suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
- a suitable dosage level is about 1.0 mg to l ⁇ g per day, preferably about ⁇ .O mg to
- the compounds may be administered on a regimen of 1 to 4 times per day.
- the invention further provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in treatment of the human or animal body.
- said treatment is for a condition which is
- the compounds of the present invention will be of use in the prevention or treatment of diseases and conditions in which pain and/or inflammation predominates, including chronic and acute pain conditions.
- diseases and conditions include rheumatoid arthritis; osteoarthritis; post-surgical pain; musculo-skeletal pain, particularly after trauma; spinal pain; myofascial pain syndromes; headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; ear pain; episiotomy pain; burns, and especially primary hyperalgesia associated 5 therewith; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, pain associated with cystitis and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve
- peripheral neuropathies peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; itching conditions including pruritis, itch due to hemodialysis, and contact dermatitis; pain (as well as broncho-constriction and inflammation) due to exposure (e.g.
- neuropathic pain conditions such as diabetic neuropathy, chemotherapy-induced neuropathy and post-herpetic neuralgia; "non-painful" neuropathies; complex regional pain syndromes; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage, low back pain, sciatica and
- ankylosing spondyHtis gout
- scar pain irritable bowel syndrome
- inflammatory bowel disease urinary incontinence including bladder detrusor hyper-refl-exia and bladder hypersensitivity
- respiratory diseases including chronic obstructive pulmonary disease (COPD), chronic bronchitis, cystic fibrosis and asthma; autoimmune diseases; and immunodeficiency disorders.
- COPD chronic obstructive pulmonary disease
- the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment or prevention of physiological disorders that may be amehorated by modulating VRl activity.
- the present invention also provides a method for the treatment or
- the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates.
- the present invention also provides a method for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) or a composition comprising a compound of for ⁇ mla (I).
- any of the aforementioned conditions may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition.
- the compound of formula (I) and the other pharmacologically active agent(s) may be l ⁇ administered to a patient simultaneously, sequentially or in combination.
- a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs, including selective cyclooxygenase-2 (COX- 2) inhibitors, as well as opioid
- analgesics especially morphine, NR2B antagonists, bradykinin antagonists, anti-migraine agents, anticonvulsants such as oxcarbazepine and carbamazepine, antidepressants (such as TCAs, SSRIs, SNRIs, substance P antagonists, etc.), spinal blocks, gabapentin, pregabalin and asthma treatments (such as ⁇ 2-adrenergic receptor agonists or leukotriene D4antagonists (e.g. montelukast).
- Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, nabumetone, ketoprofen, naproxen, piroxicam and sulindac, etodolac, meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valdecoxib and tilicoxib.
- Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine,
- Suitable anti-migraine agents of use in conjunction with a compound of the present invention include CGRP-antagonists, ergotamines or ⁇ -HTi agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
- a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
- a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use
- compounds of formula (I) may be prepared by the reaction of a compound of formula (II) with a compound of formula (III): l ⁇
- the reaction is conveniently effected at a temperature between 20°C and the reflux temperature of the solvent.
- Suitable solvents include a halogenated 20 hydrocarbon, for example, dichloromethane.
- compounds of formula (I) may also be prepared by the reaction of a compound of formula (IV) with a compound of formula (V):
- compounds of formula (I), in which X is an oxygen atom may be prepared by the reaction of a compound of formula (II) with a compound of formula (VI):
- the carboxylic acid is first reacted with diphenylphosphoryl azide and triethylamine which forms the corresponding isocyanate by a Curtius rearrangement.
- the isocyanate may then be reacted in situ with the amine of formula (II) by heating at reflux to give the desired compound of formula (I).
- the reactions are conveniently effected in a suitable solvent such as an aromatic hydrocarbon, for example, toluene.
- compounds of formula (I), in which X is an oxygen atom may also be prepared by the reaction of a compound of formula (V) with a compound of formula (VII):
- compounds of formula I can be converted into other compounds of formula I utilising synthetic methodology well known in the art.
- R 2 when R 2 is a chlorine atom it can be converted to a cyano group using zinc chloride by heating, generally to about 80°C, in the presence of a catalyst such as triphenylphosphine palladium under an inert atmosphere for about three days.
- a catalyst such as triphenylphosphine palladium under an inert atmosphere for about three days.
- R 2 is a carboxylic ester it can be hydrolysed in the presence of a basic catalyst to the carboxylic acid by known methods.
- This compound can be converted to an amine group utilising diphenylphosphoryl azide, generally in the presence of a base such as triethylamine, a solvent such as dioxane, under an inert atmosphere and with heating to about 100°C for about 90 minutes, followed by the addition of water, generally with further heating, for about an hour.
- the carboxylic ester can be selectively reduced to a hydroxymethyl group with lithium borohydride, generally in a solvent, such as a mixture of tetrahydrofuran and toluene, at 60°C for about lh.
- Compounds of formulae (III) and (IV) in which X is an oxygen atom may be prepared in situ, as described in general process (C), or they may be prepared from the corresponding carboxyUc acid of formulae (VT) and (VII), respectively, by first being converted into the corresponding acyl halide by reaction with, for example, oxalyl chloride. The acyl halide is then converted into the corresponding acyl azide by reaction with, for example, with sodium azide. The desired isocyanate is then obtained by a conventional Curtius rearrangement by heating the acyl azide at reflux. The reactions are conveniently effected in a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane.
- a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane.
- compounds of formula II in which B is a nitrogen atom and A, D and E are carbon atoms, one group R 2 is present at the 3 -position and R 3 is hydrogen can be made by reacting a compound in which the amino group is l ⁇ absent with a mixture of concentrated sulfuric acid and fuming nitric acid at about 0°C for about 30 minutes followed by reduction of the resultant nitro group for example using hydrogen and Lindlar catalyst, in a solvent such as methanol.
- This compound can be made by reacting a compound of formula VIII:
- R 1 is as defined above with ammonia, generally at about 80°C for about ⁇ hours, at a pressure of about 3 ⁇ psi in a Parr apparatus.
- the compound of formula VIII can be made by successively reacting a 2 ⁇ compound of formula IX:
- R 1 is as defined above with a carbonylating agent such as dichloromethyl methylether in a solvent such as dichloromethane in the presence ⁇ of a catalyst such as titanium tetrachloride at about room temperature for about an hour.
- a carbonylating agent such as dichloromethyl methylether in a solvent such as dichloromethane in the presence ⁇ of a catalyst such as titanium tetrachloride at about room temperature for about an hour.
- the methoxy group is converted to a hydroxy group using a reagent such as borontribromide in a solvent such as dichloromethane at about room temperature for several hours.
- This compound is optionally activated, for example by forming the trifluoromethylsulfonate using trifluoromethanesulfonic 10 anhydride generally in the presence of a base such as triethylamine and a solvent such as dichloromethane for about one hour at room temperature.
- This compound is reacted with a solution
- the carbonyl moiety in the compounds of formula VIII can also be produced by selectively reducing a carboxylic acid moiety using a reagent such as borane tetrahydrofuran complex in tetrahydrofuran, at about room temperature for about 4 hours, to the alcohol followed by selective oxidation to the aldehyde
- a reagent such as borane tetrahydrofuran complex in tetrahydrofuran
- R 1 is as defined above
- R 2 is as defined above
- an acid such as concentrated sulfuric acid
- R 1 and R 2 are as defined above, is reacted with an alkylating agent, such as the appropriate Grignard reagent, generally in a solvent such as tetrahydrofuran for several hours at about room temperature followed by ehmination of water under acidic conditions, to produce the corresponding indene.
- an alkylating agent such as the appropriate Grignard reagent
- a solvent such as tetrahydrofuran
- tetrahydrofuran a solvent
- tetrahydrofuran a solvent
- This is converted to the corresponding epoxide, for example using ozone at a temperature of about -78°C for about 9% hours.
- ammonium hydroxide at about room temperature for about 2 days to produce the isoquinoline which is then nitrated and reduced to produce the amine.
- any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
- the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
- the mixture was heated at reflux for 4 hours, cooled and quenched by the sequential addition of water (25 ml), 15% aqueous NaOH (25 ml), and water (50 ml).
- the inorganic by-products were filtered off and ⁇ washed several times with diethyl ether (overall volume 1000 ml).
- the combined filtrates were dried over Na2SO , filtered and evaporated.
- the residue was dissolved in methanol (400 ml), the solution was treated with activated carbon (10 g), and the mixture was re-fluxed for 40 minutes, then filtered and evaporated.
- the residue was treated with IN HCl in ether (1000 ml), and the precipitate 10 formed was filtered, washed with ether and dried to give the title compound (63 g, 70%).
- the p ⁇ of the filtrate was adjusted from 8.6 to 12.5 by the 5 addition of 3N NaO ⁇ (100 ml) and 6N NaO ⁇ (40 ml).
- the phases were separated and to the aqueous phase was added tert-butyl methyl ether (500 ml).
- the p ⁇ of the resulting mixture was adjusted to 2 with 6N ⁇ C1 (200 ml).
- the phases were again separated and the aqueous phase was extracted with terf-butyl methyl ether (2 x 300 ml).
- the organic phases were combined, dried over MgSO 4 , filtered 0 and evaporated to give the title compound (73 g, 89%), as an off white sohd.
- the mixtiire was poured into water (600 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic layers were washed with water (3 x 300 ml), brine (200 ml) then dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5% Et2 ⁇ in iso-hexanes to give the title compound (10.38 g, 95%).
- the mixture was extracted with dichloromethane (3 x 150 ml) and the combined organic layers were washed with brine, dried over Na2SO4 and filtered through a 1 inch plug of silica gel.
- the sihca gel plug was further washed with 150 ml of a 1:1 mix of ethyl acetate and iso-hexanes.
- the combined organics were evaporated to give the title compound (1.33 g, 82%) as a brown sohd.
- 3-Methyl-5-nitroiso ⁇ uinoline 3-Methylisoquinoline (2.14 g, 14.9 mmol) was added portionwise to ice-cooled concentrated H2SO4 (10 ml) keeping the internal temperature below 10 °C. A nitrating mixture of concentrated H2SO4 (2 ml) and fuming nitric acid (2 ml) was then added dropwise keeping the internal temperature below 15 °C. After stirring for 30 minutes, TLC indicated reaction was complete. The acid was neutrahzed by adding the mixture to an excess of 4N aqueous NaOH (180 ml) with ice-cooling.
- Benzophenone imine (445 ⁇ L, 2.64 mmol) was added to a mixture of 6-bromoisoquinohne (500 mg, 2.4 mmol), BINAP (60 mg, 0.1 mmol), palladium acetate (12 mg, 0.05 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in THF (10 ml) at room temperature.
- the mixture was degassed (N2 x 3) then heated at reflux under a nitrogen atmosphere for 16 hours.
- the reaction was then cooled to room temperature, partitioned between ethyl acetate (20 ml) and water (20 ml) and the aqueous phase extracted with ethyl acetate (20 ml).
- N-(2-Bromobenzyl)-2,2-diethoxyacetamide (Description 52; 15.6 g , 49 mmol) was carefully added to concentrated H2SO4 (78 ml) with stirring at 10-20°C. The reaction mixture was stirred at room temperatxire for 16 hours, poured into ice water and filtered. The filtrate was neutralised with 33% aqueous ammonium hydroxide and the resulting precipitate was filtered and dried to give the title compound (10.1 g, 91%).
- Ureas were synthesized, unless otherwise stated, using one of 2 methods.
- a convenient procedure starts with a carboxyhc acid which, on treatment with diphenylphosphoryl azide and triethylamine, undergoes a Curtius reaction.
- the isocyanate formed in situ is then trapped by addition of an amine all in one-pot.
- ureas are synthesized by reacting an amine with a preformed isocyanate.
- Urea precursors not mentioned in Descriptions 1 to 58 are known compounds.
- Description 65 l-chloro-3-ethyl-5-nitroisoquinohne l-chloro-3-ethyhsoquinoline [see WO 01/92233] (2.0 g, 10.4 mmol) was nitrated according to the method of Description 42 to give the title compound (2.37 g, 96 %).
- Description 66 l-chloro-3-ethvhsoquinohn-5-amine l-chloro-3-ethyl-5-nitroisoquinohne (Description 65; 2.0 g, 8.4 mmol) was reduced according to the method of Description 50 to give the title compound (1.2 g, 69 %).
- Isoquinohne-1-carboxyhc acid (3.98 g, 23.0 mmol) was dissolved in cone, sulfuric acid (16 ml) at 0 °C. A mixture of cone, sulfuric acid (5 ml) and fuming nitric acid (5 ml) was added over 10 min. and the reaction stirred for a further lh at 0 °C, then poured into ice-water (400 ml). The sohd was collected by filtration, then washed with water (100 ml), ethanol (100 ml) and ether (100 ml), then dried under vacuum to give the title compound (4.1 g, 82%).
- 3-Chloroisoquinohne (Description 49; 3.4 g, 20.7 mmol) was nitrated according to the method of Description 44. After addition of the base, the sohd was filtered off to give crude 3-chloro-5-nitroisoquinohne (9 g). A sample (6.8 g) was partitioned between ethyl acetate and 10% aqueous K-2CO3 solution (200 ml). The organic layer was extracted with more ethyl acetate (100 ml) and the combined organic phases dried (Na2SO ) and evaporated to give the title compound (2.10 g, 64%).
- Ethyl 2-( ⁇ -aminoisoquinohn-3-yl)ethylcarbamate Prepared using ethyl 2-isoquinolin-3-ylethylcarbamate (Description 114) in place of 3-methyhsoquinohne according to the procedures of Descriptions 44 and 43 respectively.
- N-[2-(4-tert-Butylphenyl)ethyl1-N-isoquinohn- ⁇ -ylurea Prepared from isoquinoline-5-carboxylic acid and 2-(4-te ⁇ X butylphenyl)ethylamine. m/z (ES + ) 348 (M + H) + .
- Examples 18 to 51 were prepared according to the procedure of Description 60.
- N-Isoquinohn-5-yl-iV 1 - ⁇ 2-[3-(trifluoromethyl)phenyllethyl>urea Prepared from isoquinohne- ⁇ -carboxyhc acid and 2-[3-(trifluoromethyl)phenyl]ethylamine. m/z (ES + ) 360 (M + H) + .
- N-Isoquinohn- ⁇ -yl-N- ⁇ 3-[4-(trifluoromethv phenynpropyllurea Prepared from isoquinohne-5-carboxyhc acid and ⁇ 3-[4-(trifluoromethyl)phenyl]propylamine (Description 22). m/z (ES + ) 374 (M + H) + .
- N-Isoquinohn- ⁇ -yl-N- ⁇ -ftrifluoromethyDbenzyllurea Prepared from isoquinoline-8-carboxylic acid and 4-(trifluoromethyl)benzylamine.
- N-[3-Fluoro-4-(trifluoromethyl)benzyl]-N-isoquinohn- ⁇ -ylurea 5 Prepared from isoquinohne- ⁇ -carboxyhc acid and 3-fluoro-4- (trifluoromethyl)benzylamine. m/z (ES + ) 364 (M + H) + .
- N- r2-Fluoro-4-(trifl.uoromethyl)benzyl] - JV-isoquinohn- ⁇ -ylurea 0 Prepared from isoquinoline- ⁇ -carboxyhc acid and 2-fluoro-4- (trifluoromethyl)benzylamine. m/z (ES + ) 364 (M + H) + .
- Example 24 N-Isoquinohn- ⁇ -yl-iV-r4-(trifluoromethoxy)benzyllurea Prepared from isoquinoline-5-carboxyhc acid and 4-(trifluoromethoxy)benzylamine. m/z (ES + ) 362 (M + H) + .
- Example 25 N-Isoquinohn- ⁇ -yl-iV-r4-(trifluoromethoxy)benzyllurea Prepared from isoquinoline-5-carboxyhc acid and 4-(trifluoromethoxy)benzylamine. m/z (ES + ) 362 (M + H) + .
- Example 25
- a r - ⁇ [6-(4-Fluorophenyl)pyridin-3-yl]methv -iV 1 -isoquinohn-5-ylurea Prepared from isoquinohne- ⁇ -carboxyhc acid and [6-(4-fluorophenyl)pyridin-3- yl]methylamine (Description 26). m/z (ES + ) 373 (M + H) + .
- Example 26 ⁇ r -Isoquinohn-8-yl-iV- ⁇ 3-r4-(trifluoromethyl)phenyllpropyl)urea Prepared from isoquinohne-8-carboxyhc acid and 3-[4-(trifluoromethyl)phenyl]propylamine (Description 22). m/z (ES + ) 374 (M + H) + .
- N-Quinolin- ⁇ -yl-N- ⁇ 3-[4-(trifluoromethyl)phenyl]propyl)urea Prepared from quinohne-5-carboxyhc acid and 3-[4-(trifluoromethyl)phenyl]propylamine (Description 22). m/z (ES + ) 374 (M + H) + .
- N-Isoquinohn-8-yl-N-(3-r3-(trifluoromethyl)phenvnpropyl)urea Prepared from isoquinohne-8-carboxyhc acid and
- Example 29 N-Quinohn-5-yl-iV-l3-[3-(trifluoromethyl)phenyl1propyl)urea Prepared from quinohne- ⁇ -carboxyhc acid and 3-[3-(trifluoromethyl)phenyl]propylamine (Description 23). m/z (ES + ) 374 (M + H) + .
- N-Isoquinohn-8-yl-N-r4-(trifluoromethoxy)benzyllurea Prepared from isoquinohne-8-carboxyhc acid and 4-(trifluoromethoxy)benzylamine. m/z (ES + ) 362 (M + H) + .
- N-(2.3-Dihvdro- lH-inden-2-ylmethyl)-iV-isoquinohn-5-ylurea Prepared from isoquinoline- ⁇ -carboxyhc acid and 2,3-dihydro-lH-inden-2- 10 ylmethylamine. m/z (ES + ) 318 (M + ⁇ ) + .
- N-Isoquinohn- ⁇ -yl-N-(6.7.8.9-tetrahvdro-5H-benzo[ ]r71annulen-6-ylmethyl)urea Prepared from isoquinohne- ⁇ -carboxyhc acid and 6,7,8,9-tetrahydro- ⁇ H- 20 benzo[ ⁇ ][7]annulen-6-ylmethylamine hydrochloride (Description 26). m/s (ES + ) 346 (M + ⁇ ) + .
- N-Isoquinohn-5-yl-JV , -(6.7.8.9-tetrahydro- ⁇ H-benzo[ ⁇ ir71annulen-7-ylmethyl)urea 25 Prepared from isoquinohne-5-carboxyhc acid and 6,7,8,9-tetrahydro- ⁇ H- benzo[ ] [7] annulen- 7-ylmethylamine hydrochloride (Description 28). m/z (ES + ) 346 (M + ⁇ )+.
- N-Isoquinohn-5-yl-JV- ⁇ [6-(trifluoromethyl)pyridin-3-yllmethyllurea Prepared from isoquinoline-5-carboxyhc acid and 3-aminomethyl-6- (trifluoromethyl)pyridine. m/z (ES + ) 347 (M + H) + .
- N-(8-Fluoroisoquinohn- ⁇ -yl)-JV-r4-(trifluoromethyl)benzyl]urea Prepared from 8-fluoroisoquinohn-5-amine (Description 43) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES + ) 364 (M + H) + .
- N-Isoquinohn- ⁇ -yl-N-methyl-JV- ⁇ -faifluoromethvDbenzyllurea Sodium hydride (60 % dispersion in oil, 7 mg, 0.17 mmol) was added to a suspension N-isoquinolin- ⁇ -yl-JV-[4-(trifluoromethyl)benzyl]urea (Example 14; 48 mg, 0.14 mmol) in THF (3 mL) at room temperature and the reaction was stirred until effervescence ceased (20 minutes). Methyl iodide (11 ⁇ L, 0.17 mmol) was added and the reaction stirred at room temperature for 3 hours.
- JV-Isoquinolin- ⁇ -yl-N-methyl-N-[4-(trifluoromethyl)benzyl]urea Prepared from isoquinohne-5-carboxyhc acid and N-methyl-N-[4- (trifluoromethyl)benzyl] amine (Description 31). m/z (ES + ) 190 (M + H) + .
- Example 55 JV-Isoquinohn-5-yl-JV- ⁇ l-[4-(trifluoromethyl)phenyllethyl)urea Prepared from isoquinohne- ⁇ -carboxyhc acid and l-[4-(trifluoromethyl)phenyl]ethylamine (Description 32). m/z (ES + ) 360 (M + H) + .
- N-Isoquinohn-5-yl-JV-[(3-phenyl-1.2.4-oxadiazol-5-yl)methvnurea Prepared from isoquinohne-5-carboxyhc acid and (3-phenyl-l,2,4-oxadiazol-5- yl)methylamine hydrochloride (Description 34). m/z (ES + ) 346 (M + H) + .
- JV-(3-Methoxyisoquinohn-8-yl)-JV- 4-(trifluoromethyl)benzvnurea Prepared from 3-methoxyisoquinoline-8-carboxylic acid (Description 56) and 4- (trifluoromethyl)benzylamine. m/z (ES + ) 376 (M + H) + .
- Example 61 JV-Cinnohn-5-yl-JV-r4-(trifluoromethyl)benzyllurea Prepared from cinnohn-5-amine (Sci Pharm. 1982, 50, 246) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES + ) 347 (M + H) + .
- Examples 62 to 64 were prepared according to the procedure of Description 60.
- JV-(l-Chloroisoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzvnurea Prepared from l-chloroisoquinohn-5-amine (Description 48) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES + ) 380, 382 (M + H) + .
- N-[l-(Dimethylamino)isoquinohn-5-yll-JV-[4-(trifluoromethyl)benzyl]urea N-(l-Chloroisoquinohn-5-yl)-N-(4-trifluoromethylbenzyl)urea (Example 69; 60 mg) was suspended in ethanol (5 ml). Ethanohc dimethylamine (33%, 2 ml) was added and the mixture heated to 100 °C in a sealed tube for 16 hours after which time TLC indicated complete reaction. The reaction mixture was evaporated and the residue purified by preparative thin layer chromatography (5% methanol-dichloromethane eluant) to give the title compound (20 mg). m/z (ES + ) 389 (M + H) + .
- JV-(3-Methvhsoquinohn- ⁇ -yl)-JV-[4-(trifluoromethoxy)benzyl]urea Prepared from 3-methyhsoquinolin-5-amine (Description 46) and [4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES + ) 376 (M + H) + .
- JV-(3-Chloroisoquinohn- ⁇ -yl)-JV-[4-(trifluoromethyl)benzvnurea Prepared from 3-chloroisoquinohn-5-amine (Description 60) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES + ) 380, 382 (M + H) + .
- Example 74 JV-(3-Methylcinnohn- ⁇ -yl -JV-[4-(trifluoromethyl)benzyl1urea Prepared from 3-methylcinnolin-5-amine and [4-(trifluoromethyl)benzyl]isocyanate (Description 68) according to the procedure of Description 61. m/z (ES + ) 361 (M + H) + .
- N-(l-chloroisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea (Example 69; 47 mg, 0.12 mmol) was added to a mixture of 3N HCl (aq. 5 ml) and THF (1 ml). The mixture was heated at 90 °C for 20 hours, then 6N HCl (aq. 2 ml) was added and the reaction heated at 90 °C for a further 20 hours. After coohng to room temperature, ethyl acetate (20 ml) was added and the layers separated (some sohd was suspended in the organic layer).
- N-f4-(trifluoromethyl)benzyl1-JV-[3-(trifluoromethyl)isoquinohn-5-yllurea Prepared from 3-(trifluoromethyl)isoquinohn-5-amine (Description 64) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES + ) 414 (M + H) + .
- N-(l-chloro-3-ethyhsoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzyllurea Prepared from l-chloro-3-ethyhsoqx ⁇ inolin-5-amine (Description 66) and [4- (trifluoromethyl)benzyl] isocyanate (Description 58) according to the procedure of Description 61. m/z (ES + ) 408 , 410 (M + H) + .
- N-(1.3-benzodioxol- ⁇ -yl)-N'-[quinohn-6-yl]urea Prepared from 6-aminoquinohne and 3,4-(methylenedioxy)phenyl isocyanate. m/z (ES + ) 308 (M + H) + .
- N-cyclohexyl-N'- [qx ⁇ inolin-6-yll urea Prepared from 6-aminoquinohne and cyclohexyl isocyanate. m/z (ES + ) 270 (M + H) + .
- CHO cells stably expressing recombinant human VRl receptors and plated into black-sided 384-well plates, were washed twice with assay buffer (Hepes-buffered sahne) and then incubated with luM Fluo-3-AM for 60 minutes in darkness. Cells were washed twice more to remove excess dye, before being placed, along with plates containing capsaicin and test compounds in a Molecular Devices FLIPR.
- the FLIPR simultaneously performed automated pharmacological additions and recorded fluorescence emmission from Fluo-3. In all experiments, basal fluorescence was recorded, before addition of test compounds and subsequent addition of a previously determined concentration of capsaicin that evoked 80% of the maximum respsonse.
- hyperalgesia is defined as the difference in paw withdrawal latencies for sahne/vehicle- and carrageenan/vehicle-treated rats. Paw wthdrawal latencies for drug treated rats are expressed as a percentage of this response. Statistical analysis is performed using one-way ANOVA foUowed by Dunnett's test; p values ⁇ 0.05 compared to carrageenan/vehicle-treated rats are considered significant.
- JV-(l-Methylisoquinohn- ⁇ -yl)-JV-[4-(trifluoromethyl)benzyl1urea Prepared from l-methyhsoquinohn-5-amine (Description 68) and [4-(trifluoromethyl)benzyl]isocyanate (Description 68) according to the procedure of Description 61. m/z (ES + ) 360 (M + H) + .
- N-(l-Methyhsoquinohn- ⁇ -yl)-JV-[4-(trifluoromethoxy)benzyllurea Prepared from 1-methyhsoquinolin- ⁇ -amine (Description 68) and [4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES + ) 376 (M + H) + .
- N-(6.8-Difluoro-3-methvhsoquinohn-5-yl)-N'-r4-(trifluoromethyl)benzyllurea Prepared from 6,8-difluoro-3-methyhsoquinohn-5-amine (Description 73) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES + ) 396 (M + H) + .
- Example 97 N-(8-Fluoro-3-methvhsoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzvnurea Prepared from 8-fluoro-3-methyhsoquinohn- ⁇ -amine (Description 76) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES + ) 378 (M + H) + .
- Example 98 N-(8-Fluoro-3-methvhsoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzvnurea Prepared from 8-fluoro-3-methyhsoquinohn- ⁇ -amine (Description 76) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES + ) 378 (M + H) +
- N-(6-Fluoro-3-methyhsoquinohn-5-yl)-JV-[4-(trifl.uoromethyl)benzyl]urea Prepared from 6-fluoro-3-methyhsoquinohn- ⁇ -amine (Description 79) and [4- ⁇ (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES + ) 378 (M + H) ⁇ .
- JV-(7-Chloro-3-methyhsoquinohn-5-yl)-JV-[4-(trifl.uoromethv benzvnurea Prepared from 7-chloro-3-methyhsoq ⁇ inohn- ⁇ -amine (Description 86) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES + ) 394 (M + H) + .
- N-(7-Chloroisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzvnurea Prepared from 7-chloroisoquinohn-5-amine (Description 87) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES + ) 380 (M + H) + .
- N-(8-Fluoro-3-methoxyisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea Prepared from 8-fluoro-3-methoxyisoquinoline- ⁇ -carboxylie acid (Description 88) and 4-(trifluoromethyl)benzylamine according to Description 60. m/z (ES + ) 394 (M + H) + .
- JV-(6-Fluoroisoquinohn- ⁇ -yl)-JV-[4-(trifluoromethoxy)benzyl]urea Prepared from 6-fluoroisoquinolin-5-amine (Description 89) and [4- (trifluoromethoxy)benzyl]isocyanate (Description 69) according to Description 61. m/z (ES + ) 394 ( M + B.)f
- N-(4-Methyhsoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea Prepared from 4-methyhsoquinohn-5-amine (Description 91) and [4- (trifluoromethyl)benzyl]isocyanate (Description 68) according to Description 61. m/z (ES + ) 360 (M + H) + .
- N-[7-(trifiuoromethyl)isoquinohn- ⁇ -yll-JV-r4-(trifluoromethyl)benzyl1urea Prepared from 7-(trifluoromethyl)isoquinohn-5-amine (Description 99) and [4- (trifluoromethyl)benzyl]isocyanate (Description 68) according to Description 61. m/z (ES + ) 414 (M + H) + .
- N-[7-(trifluoromethyl)isoquinohn-5-yl1-JV-r4-(trifluoromethoxy)benzyl]urea Prepared from 7-(trifluoromethyl)isoquinolin- ⁇ -amine (Description 99) and [4- (trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. l ⁇ m/z (ES + ) 414 (M + H) + .
- N-(6-Fluoro-l-methvhsoquinohn- ⁇ -v -N'-[4-(trifluoromethyl)benzyl1urea Prepared from 6-fluoro-l-methyhsoquinohn-5-amine (Description 103) and [4- 20 (trifluoromethyl)benzyl]isocyanate (description 68) according to the procedure of description 61. m/z (ES + ) 378 (M + H) + .
- N-(l-Cyanoisoqx ⁇ ol-in-5-yl -N , -f4-(trifluoro ⁇ nethyl)benzyl]urea 25 To a solution of N-(l-cHoroisoquinolin-5-yl)-N-[4-(trifluoromethyl)benzyl]urea
- N-Q-Carboxyisoquinolin-S-yh-N'-f ⁇ faifluoromethyl ⁇ benzyllurea 10 N-[l-(Methoxycarbonyl)isoquinohn-5-yl]-N-[4-(trifluoromethyl)benzyl]urea (Example 116, ⁇ mg, 0.136 mmol) was dissolved in a mixture of THF (3 ml), methanol (1 ml) and water (1 ml), then hthium hydroxide monohydrate (6 mg, 0.14 mmol) was added.
- N-(l-Aminoisoquinohn- ⁇ -yl)-N'- 4-(trifluoromethyl)benzynurea A mixture of N-(l-carboxyisoquinolin-5-yl)-N'-[4-(trifluoron ⁇ ethyl)ber ⁇ zyl]urea (Example 117, 309 mg, 0.794 mmol), diphenylphosphoryl azide (210 ⁇ l, 0.975 mmol) and Methyla ine (210 ⁇ l, 1.50 mmol) in 1,4-dioxane (25 ml) was heated at 100 °C,
- N-(3-Carboxyisoquinolin-5-yl)-N'-[4-(trifluoromethyl)benzyllurea Prepared from N-[3-(methoxycarbonyl)isoquinolin-5-yl]-N'-[4-
- N-r3-(2-Aminoethyl)isoquinohn-5-yll-JV-r4-(trifluoromethyl)benzvnurea To a solution of terf-butyl 2-(5-aminoisoquinohn-3-yl)ethylcarbamate (Description 116; 200 mg, 0.7 mmol) in deuterated chloroform ( ⁇ ml) was added [4- (trifluoromethyl)benzyl]isocyanate (0.506M solution in DCM) (Description 58; 1.38 ml, 0.7 mmol), and the resulting mixture heated at reflux overnight. The reaction mixture was cooled and the precipitate removed by filtration, washed with DCM and dried.
- the reaction was then cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with more ethyl acetate (50 ml) and the combined organic layers were evaporated. The residue was taken up in tetrahydrofuran (40 ml) and 2N hydrochloric acid (aq. 10 ml) was added. After 2h, the THF was evaporated, 3N hydrochloric acid (aq. 100 ml) was added and the mi-xture washed with ethyl acetate (2 x 75 ml).
- Example 128 5 N-Isoquinohn- ⁇ -yl-JV- ⁇ 2-(trifluoromethyl)pyrimidin-5-yllmethyl
- N-Isoquinohn- ⁇ -yl-JV-[4-(morphohn-4-ylmethyl)benzyllurea A solution of isoquinohne- ⁇ -carbonyl azide (Description 126, 60 mg, 0.2 ⁇ mmol) in toluene (5 mL) was heated at 76 °C for 1 h. The reaction was cooled to 50 °C and 4-(morphohn-4-ylmethyl)benzylamine (Description 123, 0.31 mmol) was added as a solution in CH2CI2 (1 ml). The precipitated product was coUected by filtration and washed with hexane, then further purified using mass-directed HPLC to give the title compound (2.5 mg, 3%). m/z (ES + ) 376 (M + H) + .
- N-Isoquinohn-5-yl-JV-[2-(2-morpholin-4-ylethoxy)-4-(trifluoromethyl)benzyllurea A solution of isoquinohne- ⁇ -carbonyl azide (Description 126, 43 mg, 0.22 mmol) in toluene (4 mL) was heated at 80 °C for 50 min. The reaction was cooled to 50 °C and 2-(2-morphohn-4-ylethoxy)-4-(trifluoromethyl)benzylamine (Description 125, 66 mg, 0.22 mmol) was added as a solution in toluene (1 ml). The precipitated product was coUected by filtration and washed with dichloromethane to give the title compound (83 mg, 80%). m/z (ES + ) 475 (M + H) + .
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Abstract
The present invention provides compounds of formula (I); pharmaceutically acceptable salts and N-oxides thereof in which A, B, D and E are C or N with the proviso that one or more are N, R1, R2, R3, R4, R5 and R6 are simple substituents, n is 0-3 and y is an aryl, heteroaryl, carbocyclyl or fused-carbocyclyl group; as VR-1 antagonists for treating conditions or diseases in which pain and/or inflammation predominates; the use of the same for manufacturing medicaments, pharmaceutical compositions comprising them and methods of treatment utilising them.
Description
HETEROROMATIC UREA DERIVATIVES AS VR-1 RECEPTOR MODULATORS FOR TREATING PAIN
The present invention is concerned with heteroaromatic ureas and 5 pharmaceutically acceptable salts and prodrugs thereof which are useful as therapeutic compounds, particularly in the treatment of pain and other conditions ameliorated by the modulation of the function of the vani loid-1 receptor (VR1).
The pharmacologically active ingredient of chilli peppers has been
10 recognised for some time to be the phenolic amide capsaicin. The application of capsaicin to mucous membranes or when injected intradermally, causes intense burning-like pain in humans. The beneficial effects of topical administration of capsaicin as an analgesic is also well established. However, understanding of the underlying molecular pharmacology mediating these responses to capsaicin has
15 been a more recent development.
The receptor for capsaicin, termed the vanilloid NRl receptor, was cloned by Caterina and colleagues at UCSF in 1997 (Nature, 398:816, 1997). VE1 receptors are cation channels that are found on sensory nerves that innervate the skin, viscera, peripheral tissues and spinal cord. Activation of NRl elicits action
20 potentials in sensory fibres that ultimately generate the sensation of pain.
Importantly NRl receptor is activated not only by capsaicin by also by acidic pH and by noxious heat stimuli and thus appears to be a polymodal integrator of painful stimuli.
The prototypical NRl antagonist is capsazepine (Walpole et al,
25 J. Med. Chem., 37:1942, 1994). This has only micromolar affinity for NRl and is non-specific in its action. A novel series of sub-micromolar antagonists has also been reported recently (Lee et al, Bioorg. Med. Chem., 9:1713, 2001), but these reports provide no evidence for in vivo efficacy. A much higher affinity antagonist has been derived from the 'ultra-potent' agonist resiniferatoxin.
30 Iodo-resiniferatoxin (Wahl et al, Mol. Pharmacol, 59:9, 2001) is a nanomolar antagonist of NRl but does not possess properties suitable for an oral pharmaceutical. This last is also true of the micromolar peptoid antagonists described by Garcia-Martinez (Proc. Natl. Acad. Sci., USA, 99:2374, 2002). Most recently International (PCT) patent publication No. WO 02/08221 has described a
novel series of NRl antagonists, which are stated to show efficacy in a number of animal models. We herein describe another novel series of NRl modulators. These comprise predominantly NRl antagonists but encompass NRl partial antagonists and NRl partial agonists. Such compounds have been shown to be efficacious in animal models of pain.
Structurally related compounds are disclosed in EP-A-0418071, WO-A- 9104027, WO-A-9324458, US-A-5596001 and US-A-5362818 all in the name of Pfizer Inc., WO-A-0064888 and WO-A-0064876 in the name of Aventis Pharmaceutical Products Inc. and WO-A-9406280 in the name of The Regents of the University of California. None of the compounds disclosed are for treating pain.
The present invention provides compounds of formula (I):
(I) wherein
A, B, D and E are each C or N with the proviso that one or more are N; R1 and R2 are each independently hydrogen, halogen, hydroxy, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, haloCi-βalkyl, hydroxyCi-βalkyl, Ci-βalkoxy, haloCi-βalkoxy, hydroxyCi-βalkoxy, C3-7cycloalkyl, C3-5cycloalkylCι- alkyl, NR7R8, carboxy, esterified carboxy, Ci-βalkyl substituted with a group selected from NR7R8, carboxy and esterified carboxy, or Ci-βalkoxy substituted with a group selected from NR7R8, carboxy and esterified carboxy;
R8 and R4 are each independently hydrogen, Ci-βalkyl, C2-6alkenyl or C2-6alkynyl; R5 and R6 are, at each occurrence, independently hydrogen, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, Ci-βalkoxy, Ci-βacyloxy, carboxy, esterified carboxy, CONR7R8, SO2R7, SO2NR7R8, aryl, heteroaryl, heterocyclyl, or Cι-6alkyl substituted with a group selected from hydroxy, Ci-βalkoxy, Ci-βacyloxy, carboxy, esterified carboxy, NR7R8, CONR7R8, SR7, SO2R7, SO2NR7R8, aryl, heteroaryl and heterocyclyl;
or R5 and R6 and the carbon atom to which they are attached together form a carbocyclic ring of 3 to 6 carbon atoms;
R7 and R8 are, at each occurrence, independently hydrogen, Ci-βalkyl, C2-6alkenyl,
C2-6alkynyl, C3-7cycloalkyl or fluoroCi-βalkyl; or R7 and R8 and the nitrogen atom to which they are attached together form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or Cι- alkoxy, which ring may optionally contain as one of the said ring atoms an oxygen or a sulfur atom, a group S(O) or S(O)2, or a second nitrogen atom which will be part of a NH or NRa moiety where Ra is Cι- alkyl optionally substituted by hydroxy or Cι- alkoxy;
X is an oxygen or sulfur atom or the group =NCN;
Y is an aryl, heteroaryl, carbocyclyl or fused-carbocyclyl group; and n is either zero or an integer from 1 to 3; or a pharmaceutically acceptable salt, N-oxide or a prodrug thereof. R1 may be absent or one or two R1 groups may be present, as a preferred embodiment. R1 is thus preferably chosen independently from halogen, haloCi- βalkyl and Ci-ealkoxy, such as fluorine, chlorine, trifluoromethyl and methoxy. A preferred class of compound of formula (I) is that wherein R1 is a hydrogen or halogen atom or a group selected from Ci-βalkyl and Ci-βalkoxy. More particularly, a preferred class of compound of formula (I) is that wherein R1 is a hydrogen or a halogen atom, particularly a hydrogen or a fluorine atom, and most especially a hydrogen atom.
Where R1 is other than hydrogen, preferably there is only one R1 substituent. Generally R2 is absent or one or two R2 groups are present. Thus R2 is preferably independently chosen from Ci-βalkoxy, halogen, di(Cι-6alkyl)amino,
Ci-βalkyl, hydroxy, Ci-βalkoxyearbonyl, carboxy, amino, haloCi-βalkyl, hydroxyCi-ealkyl and aminoCi-ealkyl. More preferably R2 is independently chosen from halogen, hydroxy, carboxy, amino, Cι-3alkoxy, di(Cι-3alkyl)amino, Ci-aalkyl, Cι-3alkoxyearbonyl, haloCι-3alkyl, hydroxyCι-3alkyl and aminoCι-3alkyl. R2 is particularly chosen independently from methoxy, methyl, ethyl, chlorine, dimethylamino, hydroxy, trifluoromethyl, methoxycarbonyl, carboxy, amino, hydroxymethyl and aminoethyl.
Another preferred class of compound of formula (I) is that wherein R2 is a hydrogen or halogen atom or a group selected from Ci-βalkyl, haloCi-ealkyl, Ci-ealkoxy, NR7R8, Ci-ealkyl substituted with NR7R8, and Ci-βalkoxy substituted with NR7R8, wherein R7 and R8 each independently preferably represent hydrogen atoms or Cι-4alkyl groups.
A further preferred class of compound of formula (I) is that wherein R2 is a hydrogen or a halogen atom, or a group selected from Cι-4alkyl, C1.4aIk.oxy and NR7R8, wherein R7 and R8 each independently preferably represent hydrogen atoms or Cι-4alkyl groups. More particularly, R2 preferably represents a hydrogen or chlorine atom or a group selected from methyl, methoxy and dimethylamino. Most preferably, R2 is a hydrogen atom.
Where R2 is other than hydrogen, preferably there is only one R2 substituent. Thus quinoline, isoquinoline and cinnoline moieties included within the scope of the invention include isoquinolin-5-yl, isoquinolin-8-yl, quinolin-5-yl, 2-oxidoisoquinolin-5-yl, 3-methoxyisoquinolin-8-yl, cinnolin-5-yl, 3- methylisoquinohn-5-yl, l-chloroisoquinolin-5-yl, l-dimethylaminoisoquinolin-5-yl, 3-methylisoquinoHn-8-yl, 3-chloroisoquinolin-5-yl, 3-methylcinnolin-5-yl, 8- fl.uoroisoquinolin-5-yl, l-hydroxyisoquinoHn-5-yl, 3-trifluoromethylisoquinolin-5- yl, l-chloro-3-ethyHsoquinolin-5yl, l-methylisoquinolin-5-yl, 6,8-dϋluoro-3- methylisoquinolin-5-yl, 7-trifluoromethyl-3-methyhsoquinolin-5-yl, 3-methyl-8- fluoroisoquinohn-5-yl, 3-methyl-6-fluoroisoquinolin-5-yl, 7-methoxyisoquinolin-5- yl, l,3-dimethyHsoquinoUn-5-yl, 3-methyl-7-chloroisoquinolin-5-yl, 7- chloroisoquinohn-5-yl, 6-fluoroisoquinolin-5-yl, 7-fluoroisoquinolin-5-yl, 4- methylisoquinolin-5-yl, 8-trifl.uoromethylisoquinoUn-5-yl, 6- trifluoromethyUsoquinohn-5-yl, 7-trifluoromethyHsoquinolin-5-yl, l-methyl-6- fluoroisoquinolin-5-yl, l-chloroisoquinohn-5-yl, l-methoxycarbonyhsoquinolin-5- yl, l-carboxyisoquinolin-5-yl, l-aminoisoquinolin-5-yl, 1- hydroxymethyhsoquinoUn-5-yl, 3-methoxycarbonyhsoquinohn-5-yl, 3- carboxyisoquinolin-5-yl, 3-dimethylaminoisoquinohn-5-yl, 3-(2- aminoethyl)isoquinolin-5-yl and 8-methoxyisoquinolin-5-yl.
A further preferred class of compound of formula (I) is that wherein R3 is a hydrogen atom or a Cι-4alkyl group, particularly a hydrogen atom or a methyl group, and most especially a hydrogen atom.
A yet further preferred class of compound of formula (I) is that wherein R4 is a hydrogen atom or a Cι-4alkyl group, particularly a hydrogen atom or a methyl group, and most especially a hydrogen atom.
Another preferred class of compound of formula (I) is that wherein R5 and R6 each independently represent a hydrogen atom or a group selected from Ci-βalkyl, Cι-6alkyl substituted by a group selected from hydroxy, Ci-βacyloxy, carboxy, esterified carboxy, NR7R8 and heterocyclyl, or an aryl group
More particularly, a preferred class of compound of formula (I) is that wherein R5 and R6 each independently represent a hydrogen atom or a Cι-4alkyl or phenyl group, particularly a hydrogen atom or a methyl group, and most especially a hydrogen atom. Thus -(CR5R6)n- can represent a bond, -CH2-, -(CEfeV, -(CH.2)3-,
-CH(C6H5)CH2CH2-, -CHCHs- and -CH(CH2COOCH2CH3)-.
A further preferred class of compound of formula (I) is that wherein X is an oxygen atom. X may be sulphur or oxygen.
A yet further preferred class of compound of formula (I) is that wherein Y is an aryl group selected from unsubstituted phenyl or naphthyl and phenyl or naphthyl substituted by one or two substituents selected from halogen, Cι-4alkyl, Cι-4alkoxy, haloCι.4alkyl, haloCι-4alkoxy, phenyl, cyano, nitro, pyrazolyl, di(Cι-6alkyl)amino, phenoxy, -OCH2O- and Ci-βalkylcarbonyl; or a heteroaryl group selected from pyridyl, thiazolyl, isoxazolyl, oxadiazolyl and pyrazolyl wherein each heteroaryl group is optionally substituted with one or two substituents selected from Cι-4alkyl, Cι-4alkoxy, haloCι-4alkyl, haloCι-4alkoxy, unsubstituted heteroaryl or phenyl which may be substituted by Ci-ealkyl or halogen; or a carbocyclyl group which is a C5-7cycloalkyl radical that is unsubstituted or substituted by a phenyl ring; or a fused-carbocyclyl group which is a Cδ-7cycloalkyl radical that is fused to a phenyl ring.
A yet further preferred class of compound of formula (I) is that wherein Y is an aryl group selected from unsubstituted phenyl and phenyl substituted by one or two substituents selected from halogen, Cι-4alkyl, Cι.4a]koxy, haloCι-4alkyl, haloCι-4alkoxy, phenyl and pyrazolyl; or a heteroaryl group selected from pyridyl,
thiazolyl, isoxazolyl, oxadiazolyl and pyrazolyl wherein each heteroaryl group is optionally substituted with one or two substituents selected from Cι-4alkyl, Cι-4alkoxy, haloCι.4alkyl, haloCι-4alkoxy, phenyl; or a carbocyclyl group which is a C5-7cycloalkyl radical that is unsubstituted or substituted by a phenyl ring; or a fused-carbocyclyl group which is a C5-7cycloalkyl radical that is fused to a phenyl ring.
Thus Y can be phenyl, biphen-4-yl, biphen-3-yl, l,2,3,4-tetrahydronaphthalen-2-yl, 4-chlorophenyl, 3,5-di(trifl.uoromethyl)phenyl, 3,4-dime hylphenyl, 4-tertbutylphenyl, 3-tertbutylphenyl, 3- trifluoromethylphenyl, 4-triQ.uoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 2, 3-dihydro- lH-inden-2-yl, 4-phenylcyclohexyl, 6, 7, 8, 9-tetrahydro-5H- benzo [a] [7] annulen-6-yl, 6, 7, 8, 9-tetrahydro-5H-benzo[a] [7] annulen- 7-yl, 3-trifLuoromethylpyridin-6-yl, 4-tertbutylpyridin-6-yl, 2-tertbutylpyridin-5-yl, 2-tertbutylpyridin-4-yl, 2-tertbutylpyridin-6-yl, 2-trifluoromethylpyridin-5-yl, 2-(pyrazol-l-yl)phenyl, 4-(pyrazol-l-yl)phenyl, 2-phenylthiazol-5-yl, 2-(thiophen- 2-yl)thiazol-3-yl, 3-phenylthiazol-2-yl, 5-phenyHsoxazol-3-yl, 3-phenylisoxazol-5- yl, 3-phenyloxadiazol-5-yl, 2-benzylthiazol-4-yl, l-(2-methylphenyl)pyrazol-4-yl, cyclohexyl, naphthalen-2-yl, 4-cyanophenyl, 4-nitrophenyl, 4-dimethylaminophenyl, 4-phenoxyphenyl, l,3-benzodioxol-5-yl, 4-methylcarbonylphenyl, isoquinolin-6-yl, 4-(morpholin-4-ylmethyl)phenyl and 2-(2-morpholin-4-ylethoxy)phenyl.
Another preferred class of compound of formula (I) is that wherein one of A, B, D and E is a nitrogen atom and the other three are carbon atoms, or A and B are nitrogen atoms and D and E are carbon atoms. It will be appreciated that the group R2 is attached to any available carbon atom represented by A, B, D and E.
When present, R7 is preferably a hydrogen atom or a Cι-4alkyl group, and R8 is preferably a hydrogen atom or a Cι.4alkyl group, or the group NR7R8 represents a heteroaliphatic ring selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorphohnyl, piperazinyl or a piperazinyl group substituted on the nitrogen atom by Cι-4alkyl optionally substituted by hydroxy or Cι-4alkoxy. More preferably, the group NR7R8 represents a group selected from -NH2- -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH)CH2CH3 and -N(CH2CH3)2, and most especially, -N(CH-3)2.
One favoured class of compound of the present invention is that of formula (la) and pharmaceutically acceptable salts, N-oxides and prodrugs thereof:
da)
With reference to formula (la), preferably E is a carbon atom. Also preferred are those compounds of formula (la) where E is a carbon atom, one of A, B and D is a nitrogen atom and the others are carbon atoms, or where A and B are nitrogen atoms and D and E are carbon atoms.
Another favoured class of compound of the present invention is that of formula (lb) and pharmaceutically acceptable salts, N-oxides and prodrugs thereof:
cn>)
With reference to formula (lb), preferably E is a carbon atom. Also preferred are those compounds of formula (lb) where E is a carbon atom, one of A, B and D is a nitrogen atom and the others are carbon atoms, or where A and B are nitrogen atoms and D and E are carbon atoms. With reference to compounds of formula (lb), preferably, A is a nitrogen atom and B, D and E are carbon atoms.
When any variable occurs more than one time in formula (I), formula (la) or formula (lb) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
As used herein, the term "hydroxyCi-ealkyl" means a Ci-βalkyl group in which one or more (in particular 1 to 3, and especially 1) hydrogen atoms have been replaced by hydroxy groups. Particularly preferred are hydroxyCι-3alkyl groups, for example, CH2OH, CH2CH2OH, CH(CH3)OH or C(CH3)2OH, and most especially CH2OH.
As used herein, the terms "haloCi-θalkyl" and "haloCi-βalkoxy" means a Ci-βalkyl or Ci-βalkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. Preferred are fluoroCi-βalkyl and fluoroCi-βalkoxy groups, in particular, fl.uoroCι-3alkyl and fl.uoroCι-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3. OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3.
The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Suitable C3-7cycloalkylCι-4alkyl groups include, for example, cyclopropylmethyl and cyclohexylmethyl.
Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is acetylene or propargyl.
When used herein, the term "halogen" means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated. When used herein, the term "carboxy" as a group or part of a group denotes CO2H.
When used herein, the term "esterified carboxy" denotes a Ci-ealkoxy or a haloCi-ealkoxy radical attached via the oxygen atom thereof to a carbonyl (C=O) radical thus forming a Ci-βalkoxycarbonyl or haloCi-βalkoxycarbonyl radical.
Suitable examples of such esterified carboxy groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
When used herein, the term "acyloxy" denotes a Ci-βalkyl or a haloCi-ealkyl radical attached to a carbonyl (C=O) radical thus forming a Ci-βalkoyl or haloCi-βalkanoyl radical which is attached via the carbonyl (C=O) radical to an oxygen atom. Suitable examples of such esterified carboxy groups include, for example, acetoxy, propionyloxy, isopropionyloxy and trifluoroacetoxy.
As used herein, the term "aryl" as a group or part of a group means an aromatic radical such as phenyl, biphenyl or naphthyl, wherein said phenyl, biphenyl or naphthyl group may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci-βalkyl, Ci-βalkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR7R8, benzyl, NO2, cyano, SRb, SOR , SO2Rb, CORb, CO2Rb, CONR Rc, C2-6alkenyl, C^alkynyl, Cι-4alkoxyCι-4alkyl, -O(CH2)mO- or a heteroaromatic group selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyridyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy (where Rb and Rc each independently represent hydrogen, Cι-4alkyl, C3-scycloalkyl or fluoroCι.4alkyl or Rb and Rc, together with the nitrogen atom to which they are attached form a piperidine, piperazine or morpholine ring and m is 1 or 2).
As used herein, the term "aryl" as a group or part of a group means an aromatic radical such as phenyl, biphenyl or naphthyl, wherein said phenyl, biphenyl or naphthyl group may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci-βalkyl, Ci-βalkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR7R8, benzyl, NO2, cyano, SR , SORb, SO2Rb, CORb, CO2Rb, CONRbRc, C2.6alkenyl, C2-6alkynyl, Cι-4alkoxyCι.4alkyl, -O(CH2)mO- or a heteroaromatic group selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyridyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy (where Rb and Rc each independently represent hydrogen, Cι-4alkyl, Cs-scycloalkyl or fluoroCι-4alkyl and m is 1 or 2).
Preferably said phenyl, biphenyl or naphthyl group is optionally substituted by one or two substituents, especially none or one. Particularly
preferred substituents include fluorine, chlorine, Cι-4alkyl (especially methyl or t-butyl), Cι-4alkoxy (especially methoxy), trifluoromethyl or trifiuoromethoxy.
As used herein, the term "heteroaryl" as a group or part of a group means a 5 or 6-membered monocyclic heteroaromatic radical containing from 1 to 4 nitrogen atoms or an oxygen atom or a sulfur atom, or a combination thereof, or an 8- to 10-membered bicyclic heteroaromatic radical containing from 1 to 4 nitrogen atoms or an oxygen atom or a sulfur atom or a combination thereof. Suitable examples include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl and cinnolinyl, wherein said heteroaromatic radicals may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci-βalkyl, Ci-βalkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR7R8, phenyl, phenyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy, benzyl, NO2, cyano, SRb, SORb, SO2 b, CORb, CO2R , CONR Rc, C^alkenyl, C^alkynyl, Cι.4alkoxyCι- alkyl, -O(CH2)mO- or an additional heteroaromatic group selected from furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyridyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy (where Rb, Rc and m are as previously defined). Preferably said heteroaromatic radical is optionally substituted by one or two substituents, especially none or one. Particularly preferred substituents include Cι-4alkyl (especially methyl or tert-butyl), Cι-4alkoxy (especially methoxy), trifluoromethyl, trifiuoromethoxy, phenyl, phenyl substituted by halogen (especially fluorine) and Cι-4alkyl (especially methyl), benzyl, or thienyl.
As used herein, the term "carbocyclyl" as a group or part of a group means a 3 to 7-membered cycloalkyl radical such as cyclobutyl, cyclopentyl or cyclohexyl, wherein said cycloalkyl radical may be optionally substituted by one, two or three groups independently selected from halogen, hydroxy, Ci-βalkyl, Ci-ealkoxy, haloCi-ealkyl, haloCi-ealkoxy, NR7R8, phenyl, phenyl substituted by a group selected from halogen, haloCi-ealkyl and haloCi-ealkoxy, benzyl, NO2, cyano, NRbRc, SRb, SOR , SO2Rb, COR , CO2Rb, CONR Rc, C2.6alkenyl, C2-6alkynyl, Cι-4alkoxyCι-4alkyl, -O(CH.2)mO- or a heteroaromatic group selected from furanyl,
pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl or pyridyl substituted by a group selected from halogen, haloCι-6alkyl and haloCi-ealkoxy (where Rb, R° and m are as previously defined). Preferably said carbocyclyl group is optionally substituted by one or two substituents, especially none or one. A particularly preferred substituent is phenyl.
As used herein, the term "fused-carbocyclyl" as a group or part of a group means a 3 to 7-membered cycloalkyl radical such as cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, wherein said cycloalkyl radical is fused to an aryl or heteroaryl group as herein defined. Preferably, said fused-carbocylyl group is attached to the remainder of the molecule via a carbon atom of the cycloalkyl radical. Preferably, said cycloalkyl radical is fused to a phenyl or pyridyl ring where said phenyl ring is optionally substituted by a group selected from halogen (especially fluorine) and fl.uoroCι.4alkyl (especially trifluoromethyl), furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, and said pyridyl ring is optionally substituted by a group selected from halogen (especially fluorine) and fl.uoroCι.4alkyl (especially trifluoromethyl). Preferably said cycloalkyl radical is fused to a phenyl ring. Particular compounds of the invention include:
N-benzyl-iV-isoquinoHn-5-ylurea
N-(l,l'-biphenyl-4-ylmethyl)-N1-isoquinohn-5-ylurea
N-(l,r-biphenyl-3-ylmethyl)-N-isoquinoHn-5-ylurea
N-isoquinolin-5-yl-iV1-(3-phenylpropyl)urea; N-isoqιύnolin-5-yl-N-(l,2,3,4-tetrahydronaphthalen-2-ylmethyl)urea;
N-[2-(4-chlorophenyl)ethyl]-N-isoquinohn-5-ylurea;
N-fS^-bis^rifluoromethy^benzylj-iV-isoquinolin-δ-ylurea;
N-[3-(3,4-dimethylphenyl)propyl]-iV,-isoquinolin-5-ylurea;
N-(4-tert-butylbenzyl)-N-isoquinolin-8-ylurea; N-(4-tert-butylbenzyl)-N-isoquinolin-5-ylurea;
N-(4-tert-butylbenzyl)-N-quinolin-5-ylurea;
N-(3-tert-butylbenzyl)-N-isoquinolin-5-ylurea;
N-[2-(4-tert-butylphenyl)ethyl]-N-isoquinohn-5-ylurea;
N-isoquinolin-5-yl-N-[4-(trifluorometlιyl)benzyl]urea;
N-isoquinohn-δ-yl-iV-fS-^riiluoromethy^benzyyurea;
N-isoquinolin-5-yl-iV1-{2-[4-(trifluoromethyl)phenyl]ethyl}urea;
N-(2-oxidoisoquinolin-5-yl)-N1-[4-(trifl.uoromethyl)benzyl]urea;
N-isoquinohn- 5 -γl-N- {2- [3-(trifl.uoromethyl)phenyl] ethyl}urea; N-isoquinohn- 5 -γl-N-{3 - [4- (trifluoromethyl)phenyl] propyl}urea;
N-isoquinolin-8-yl-IV1- [4-(trifluoromethyl)benzyl] urea;
N-[3-fl.uoro-4-(trifi.uoromethyl)benzyl]-iV1-isoquinoHn-5-ylurea;
N-[2-fl.uoro-4-(trifluoromethyl)benzyl]--Y-isoquinolin-5-ylurea;
N-isoquinolin-5-yl-iV1-{3-[3-(trrfl.uoromethyl)phenyl]propyl}urea; N-isoqxύnolin-5-yl-iV,-[4-(trifluoromethoxy)benzyl]urea;
N-{[6-(4-fluorophenyl)pyridin-3-yl]methyl}-N-isoquinolin-5-ylurea;
N-isoquinohn-8-yl-iV-{3-[4-(trifluoromethyl)phenyl]propyl}urea;
N-quinohn-δ-yl-N-lS-^-^rifluoromethy^phenyypropyllurea;
N-isoquinoHn-δ-yl-iV-fS-p-^rifluoromethy^phenyypropylJurea; N-quinohn-δ-yl-iV-lS-fS-^rifluoromethyyphenyljpropy^urea;
N-isoquinolin-8-yl-iV - [4- (trifluoromethoxy)benzyl] ure a;
N-quinoHn-δ-yl-.N-[4-(trifluoromethoxy)benzyl]urea;
N-(2, 3-dihydro- lH-inden-2-ylmethyl)-N-isoquinolin-5-ylurea;
N-isoquinoΗn-5-yl-N-(4-phenylcyclohexyl)urea; N-isoquinoΗn-δ-yl-N-(6,7,8,9-tetrahydro-δH-benzo[α][7]annulen-6-ylmethyl)urea;
N-isoquinoUn-δ-yl-iV1-(6,7,8,9-tetrahyα,ro-δH-benzo[α][7]annulen-7-ylmethyl)urea;
N-isoquinoΗn-δ-yl-iV,-{[δ-(trifluoromethyl)pyridin-2-yl]methyl}urea;
N-[(4-tert-butylpyri(hn-2-yl)methyl]-iV1-isoqvdnolin-δ-ylurea;
N- [(6-tert-butylpyridin-3-yl)methyl] -iV^-isoquinolin-δ-ylurea; N-[(2-ter^butylpyridin-4-yl)methyl]-iV,-isoqvιinolin-δ-ylurea;
N-[(6-tert-butylpyridin-2-yl)methyl]-N-isoqvιinolin-δ-ylurea;
N-isoquinolin-δ-yl-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}urea;
N-isoquinohn-δ-yl-iV-lS-te-^rifluoromethy^pyridin-S-yllpropylJurea;
N-isoquinolin-δ-yl-N-[3-(lH-pyrazol-l-yl)benzyl]urea; N-isoquinoΗn-δ-yl-N-[4-(lH-pyrazol-l-yl)benzyl]urea;
N-isoquinolin-δ-yl-iVt-[(2-phenyl-l,3-thiazol-δ-yl)methyl]urea;
N-isoquinoπn-δ-yl-N-[(2-thien-2-yl-l,3-thiazol-4-yl)methyl]urea;
N-isoquinoΗn-δ-yl-iV1-[(4-phenyl-l,3-thiazol-2-yl)methyl]urea;
N-isoquinolin-δ-yl-iV- [(2-phenyl- 1, 3-thiazol-4-yl)methyl] urea;
N-isoquinohn-δ-yl-iV1- [2-(4-phenyl- 1, 3-thiazol-2-yl)ethyl]urea;
N-isoquinolin-δ-yl-Λ^-[(δ-phenyhsoxazol-3-yl)methyl]urea;
N-isoquinolin-δ-yl-iV-KS-phenyUsoxazol-δ-y^methyyurea;
^(δ-fluoroisoquinohn-δ-y^-N-^-^rifluoromethy^benzyyurea; δ N-isoquinolin-δ-yl-N-methyl-iV1- [4-(trifluoromethyl)benzyl]urea;
N1 -isoquinohn-δ -yl-N-methyl-N- [4- (trifluoromethyl)benzyl] urea;
N-isoquinoHn-δ-yl-N-ll-^-^rifluoromethy^phenyllethylJurea;
N- ( 1, 3 -diphenylpropyl) -N-isoquinolin- δ-ylurea;
N-isoquinolin-δ-yl-N-[(3-phenyl-l,2,4-oxadiazol-δ-yl)methyl]urea; 10 N- [(2-benzyl- 1, 3-thiazol-4-yl)methyl] -iV-isoqxiinolin-δ-ylurea;
N-isoquinoUn-δ-yl-iV1-{[l-(2-methylphenyl)-lH-pyrazol-4-yl]methyl}urea;
^(S-methoxyisoquinohn-δ-y^-N'-^-^rifluoromethy^benzyyurea;
N-cinnoKn-δ-yl-N-[4-(trifluoromethyl)benzyl]urea;
N- (4- ter£-butylbenzyl) -N-cinnolin- δ -ylurea; lδ N-(3-cyclohexylpropyl)-N-isoquinoUn-δ-ylurea;
N-isoquinohn-δ-yl-iV1-(6, 7, 8, 9-tetrahydro-δH-benzo [a] [7] annulen- 7-yl)urea;
N-isoquinolin-δ-yl-N-[4-(trifluoromethyl)benzyl]thiourea;
N-isoquinoΗn-6-yl-N-[4-(trifluoromethyl)benzyl]urea;
N-isoquinoHn-6-yl-N-[4-(trifluoromethoxy)benzyl]urea; 20 ^(S-methyHsoquinohn-δ-y^-N-^-^rifluoromethy^benzyllurea;
N-(l-chloroisoquinolin-5-yl)-N-[4-(trifluoromethyl)benzyl]urea;
N-[l-(dimethylamino)isoquinoHn-δ-yl]-iV-[4-(trifluoromethyl)benzyl]urea;
Λ -(3-methyhsoquinolin-δ-yl)-iV,-[4-(trifluoromethoxy)benzyl]urea;
N-(3-methyHsoquinolin-8-yl)-N'-[4-(trifluoromethyl)benzyl]urea; 2δ N-(3-chloroisoquinoUn-5-yl)-N-[4-(trifluoromethyl)benzyl]urea;
N- (3-methylcinnolin- 5 -yl) -N- [4- (trifluoromethyl)benzyl] urea;
N-cinnohn-δ-yl-N-[4-(trifluoromethoxy)benzyl]urea;
^(l-hydroxyisoquinohn-δ-y^-iV-^-^rifluoromethy^benzyllurea;
N-^-^rifluoromethy^benzylj-N-tS-^rifluoromethy^isoquinohn-δ-yllurea; 30 N-(l-chloro-3-ethyHsoquinoHn-5-yl)---V-[4-(trifluoromethyl)benzyl]urea;
N-phenyl-N'- [quinolin- 6-yl] urea;
N-(2-naphthyl)-N'-[quinoMn-6-yl]urea;
N-(4-nitrophenyl)-N'-[quinohn-6-yl]urea;
N- [3, δ-bis(trifl.uoromethyl)phenyl] -N'- [quinolin-6-yl]urea;
N-(4-phenoxyphenyl)-N'-[quinohn-6-yl]urea;
N-(4-acetylphenyl)-N'-[quinolin-6-yl]urea;
N-benzyl-N'- [quinohn-6-yl]urea;
N- [quinohn-6-yl] -N'- [4-(trifluoromethoxy)phenyl] urea; δ N-(4-cyanophenyl)-N'-[quinolin-6-yl]urea;
N-(l,l'-biphenyl-4-yl)-N'-[quinohn-6-yl]urea;
N- [4-(dimethylamino)phenyl] -N'- [quinohn-6-yl] urea;
N-(l,3-benzodioxol-δ-yl)-N'-[quinolin-6-yl]urea;
N-cyclohexyl-iV'- [quinohn- 6-yl] urea; 10 N- [(+/-)- 1-phenylethyl] -N'- [quinohn-6-yl]urea;
N-(l-methylisoquinoUn-δ-yl)-Λ^-[4-(triQ.uoromethyl)benzyl]urea;
N-(l-methyHsoquinoHn-5-yl)-Λ?,-[4-(trifluoromethoxy)benzyl]urea;
^(βjδ-difluoro-S-methyHsoquinoHn-δ-y^-N-^-^rifluoromethy^benzyljurea;
N-[3-methyl-7-(trifluoromethyl)isoquinoUn-δ-yl]-iV1-[4- lδ (trifluoromethyl)benzyl]urea;
^(S-fluoro-S-methyUsoquinolin-δ-y^-iV-^-^rifluoromethy^benzyyurea;
N-(6-fluoro-3-methyhsoquino-lin-δ-yl)-iv1-[4-(trifluoromethyl)benzyl]urea;
N-(6-fl.uoro-3-methyHsoquinoUn-δ-yl)-iV1-[4-(trifluoromethoxy)benzyl]urea;
N-(3-methylcinnohn-δ-yl)-N-[4-(trifluoromethoxy)benzyl]urea; 20 N-(7-methoxyisoquinoHn-δ-yl)-iV1-[4-(trifluoromethyl)benzyl]urea;
N-(l,3-dimethylisoquinoUn-δ-yl)-N-[4-(trifluoromethyl)benzyl]urea;
N-(7-chloro-3-methyHsoquinolin-δ-yl)-iV,-[4-(trifluoromethyl)benzyl]urea;
N-(7-chloroisoquinohn-δ-yl)-iV1-[4-(trifluoromethyl)benzyl]urea;
N-(8-fluoro-3-metho-xyisoquinolin-δ-yl)-N-[4-(trifluoromethyl)benzyl]urea; 2δ N-(6-fluoroisoquinolin-δ-yl)-ΛT'-[4-(trifluoromethyl)benzyl]urea;
N-(6-fluoroisoquinohn-δ-yl)-N1-[4-(trifluoromethoxy)benzyl]urea;
N-(7-fl.uoroisoquinolin-δ-yl)-N-[4-(trifluoiOmethyl)benzyl]urea;
N-(4-methyhsoquinoUn-δ-yl)-iV1-[4-(trifluoromethyl)benzyl]urea;
N-tδ-^rifluoromethy^isoquinolin-δ-yll-N-^-^rifluoromethy^benzyyurea; 30 N-fβ-^rifluoromethy^isoquinolin-δ-yll-iV-^-^rifluoromethy^benzyyurea;
N-[7-(trifluoromethyl)isoquinohn-δ-yl]-iV1-[4-(triιluoromethyl)benzyl]urea;
N-[7-(trifluoromethyl)isoquinolin-δ-yl]-iV1-[4-(trifluoromethoxy)benzyl]urea;
N-(6-fl-uoro-l-methylisoquinolin-δ-yl)-N'-[4-(trifluoromethyl)benzyl]urea;
N-(l-cyanoisoquinolin-δ-yl)-N-[4-(trifluoromethyl)benzyl]urea;
N-[l-(methoxycarbonyl)isoquinoHn-δ-yl]-N-[4-(triQ.uoromethyl)benzyl]urea;
N-(l-carboxyisoquinohn-δ-yl)-N-[4-(trifl.uoromethyl)benzyl]urea;
N-(l-aminoisoquinoHn-δ-yl)-Λ^-[4-(trifluoromethyl)benzyl]urea;
N-fl-diydroxymethy^isoquinohn-δ-yy-A^-^-^ri luoromethy^benzyyurea; 5 N- [3-(methoxycarbonyl)isoquinolin-δ-yl] -N'- [4-(trifl.uoromethyl)benzyl]urea;
N-(3-carboxyisoqxιinolin-δ-yl)-N-[4-(trifl.uoromethyl)benzyl]urea;
N-[3-(dimethylamino)isoquinoHn-δ-yl]-iV1-[4-(trifluoromethyl)benzyl]urea;
N- [3-(2-aminoethyl)isoquinoUn-δ-yl] -N- [4-(trifl.uoromethyl)benzyl] urea;
^(S-methoxyisoquinohn-δ-y^-iV-^-^rifluoromethy^benzylJurea; 10 N-isoquinolin-7-yl-N'- [4-(trifhιoromethyl)benzyl]urea;
N-N-dϋsoquinolin-δ-ylurea;
N-isoquinoMn-δ-yl-N'-^-^rifluoromethy^phenyyurea;
N-isoquinoUn-δ-yl-N-{[2-(trifluoromethyl)pyrimidin-δ-yl]methyl}urea; ethyl 3-{[(isoquinohn-δ-ylamino)carbonyl] amino}-2- [4-(trifluoromethyl)benzyl] lδ propanoate;
3-{[(isoquinoUn-δ-ylamino)carbonyl]amino}-2-[4-(trifl.uoromethyl)benzyl]propanoic acid;
N-isoquinoUn-5-yl-iV1-[4-(morpholin-4-ylmethyl)benzyl]urea; and
N-isoquinohn-5-yl-N-[2-(2-morpholin-4-ylethoxy)-4-(trifluoromethyl)benzyl]urea; 20 or a pharmaceutically acceptable salt or N-oxide thereof.
In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula (I) will be 2δ non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound 30 according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p -toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic
group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry a acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or δ magnesium salts.
The salts may be formed by conventional means, such as by reacting the free base form of the compound of formula (I) with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by 10 exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention also includes within its scope N-oxides of the compounds of formula (I) above. In general, such N-oxides may be formed on any available nitrogen atom, and preferably on any one of A, B, D or E where they lδ represent a nitrogen atom. The N-oxides may be formed by conventional means, such as reacting the compound of formula (I) with oxone in the presence of wet alumina.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of 20 the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 198δ.
A prodrug may be a pharmacologically inactive derivative of a biologically 25 active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecxile. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or 30 reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention may have one or more asymmetric centres, and may accordingly exist both as enantiomers and as
diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, the compounds of formula (I) may also exist in tautomeric forms and the invention includes within its scope both mixtures and separate individual tautomers.
It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred classes of compound represented by formula (la) and formula (lb).
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices, suppositories, creams or gels; for oral, parenteral, intrathecal, intranasal, sublingual, rectal or topical administration, or for administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Favoured unit dosage forms contain from 1 to 500 mg, for example 1, 5, 10, 2δ, δO, 100, 300 or δOO mg, of the active ingredient. The tablets or pills of the novel composition can
be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric δ layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
10 The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or lδ suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of painful conditions such as those listed below, a suitable dosage level is about 1.0 mg to lδ g per day, preferably about δ.O mg to
20 δ g per day, and especially about 20 mg to 2 g day. The compounds may be administered on a regimen of 1 to 4 times per day.
It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the
2δ nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
The invention further provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in treatment of the human or animal body. Preferably, said treatment is for a condition which is
30 susceptible to treatment by modulation (preferably antagonism) of VRl receptors. The compounds of the present invention will be of use in the prevention or treatment of diseases and conditions in which pain and/or inflammation predominates, including chronic and acute pain conditions. Such conditions include rheumatoid arthritis; osteoarthritis; post-surgical pain; musculo-skeletal
pain, particularly after trauma; spinal pain; myofascial pain syndromes; headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; ear pain; episiotomy pain; burns, and especially primary hyperalgesia associated 5 therewith; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, pain associated with cystitis and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions,
10 amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; itching conditions including pruritis, itch due to hemodialysis, and contact dermatitis; pain (as well as broncho-constriction and inflammation) due to exposure (e.g. via ingestion, inhalation, or eye contact) of mucous membranes to capsaicin and related irritants such as tear gas, hot lδ peppers or pepper spray; neuropathic pain conditions such as diabetic neuropathy, chemotherapy-induced neuropathy and post-herpetic neuralgia; "non-painful" neuropathies; complex regional pain syndromes; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage, low back pain, sciatica and
20 . ankylosing spondyHtis; gout; scar pain; irritable bowel syndrome; inflammatory bowel disease; urinary incontinence including bladder detrusor hyper-refl-exia and bladder hypersensitivity; respiratory diseases including chronic obstructive pulmonary disease (COPD), chronic bronchitis, cystic fibrosis and asthma; autoimmune diseases; and immunodeficiency disorders.
25 Thus, according to a further aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment or prevention of physiological disorders that may be amehorated by modulating VRl activity.
The present invention also provides a method for the treatment or
30 prevention of physiological disorders that may be amehorated by modulating VRl activity, which method comprises administration to a patient in need thereof of an effective amount of a compound of formxila (I) or a composition comprising a compound of formula (I).
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates. 5 The present invention also provides a method for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) or a composition comprising a compound of forπmla (I).
10 According to a further aspect of the present invention, it may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition. The compound of formula (I) and the other pharmacologically active agent(s) may be lδ administered to a patient simultaneously, sequentially or in combination.
Thus, for example, for the treatment or prevention of pain and/or inflammation, a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs, including selective cyclooxygenase-2 (COX- 2) inhibitors, as well as opioid
20 analgesics, especially morphine, NR2B antagonists, bradykinin antagonists, anti-migraine agents, anticonvulsants such as oxcarbazepine and carbamazepine, antidepressants (such as TCAs, SSRIs, SNRIs, substance P antagonists, etc.), spinal blocks, gabapentin, pregabalin and asthma treatments (such as β2-adrenergic receptor agonists or leukotriene D4antagonists (e.g. montelukast).
2δ Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, nabumetone, ketoprofen, naproxen, piroxicam and sulindac, etodolac, meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valdecoxib and tilicoxib. Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine,
30 hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof. Suitable anti-migraine agents of use in conjunction with a compound of
the present invention include CGRP-antagonists, ergotamines or δ-HTi agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use
10 in the treatment or prevention of a disease or condition in which pain and/or inflammation predominates.
According to a general process (A), compounds of formula (I) may be prepared by the reaction of a compound of formula (II) with a compound of formula (III): lδ
(ID (III)
The reaction is conveniently effected at a temperature between 20°C and the reflux temperature of the solvent. Suitable solvents include a halogenated 20 hydrocarbon, for example, dichloromethane.
Similarly, according to a general process (B), compounds of formula (I) may also be prepared by the reaction of a compound of formula (IV) with a compound of formula (V):
(IV) (V)
The reaction is essentially effected in the same manner as general process
(A).
According to an alternative general process (C), compounds of formula (I), in which X is an oxygen atom, may be prepared by the reaction of a compound of formula (II) with a compound of formula (VI):
(VI)
The carboxylic acid is first reacted with diphenylphosphoryl azide and triethylamine which forms the corresponding isocyanate by a Curtius rearrangement. The isocyanate may then be reacted in situ with the amine of formula (II) by heating at reflux to give the desired compound of formula (I). The reactions are conveniently effected in a suitable solvent such as an aromatic hydrocarbon, for example, toluene.
Similarly, according to a general process (D), compounds of formula (I), in which X is an oxygen atom, may also be prepared by the reaction of a compound of formula (V) with a compound of formula (VII):
(VII)
The reaction is essentially effected in the same manner as general process (C). Further details of suitable procedures will be found in the accompanying
Examples. For instance, compounds of formula I can be converted into other compounds of formula I utilising synthetic methodology well known in the art. For example, when R2 is a chlorine atom it can be converted to a cyano group using zinc chloride by heating, generally to about 80°C, in the presence of a catalyst such as triphenylphosphine palladium under an inert atmosphere for about three days. When R2 is a carboxylic ester it can be hydrolysed in the presence of a basic catalyst to the carboxylic acid by known methods. This compound can be converted to an amine group utilising diphenylphosphoryl azide, generally in the presence of a base such as triethylamine, a solvent such as dioxane, under an inert atmosphere and with heating to about 100°C for about 90 minutes, followed by the addition of water, generally with further heating, for about an hour. The carboxylic ester can be selectively reduced to a hydroxymethyl group with lithium borohydride, generally in a solvent, such as a mixture of tetrahydrofuran and toluene, at 60°C for about lh. Compounds of formulae (III) and (IV) in which X is an oxygen atom may be prepared in situ, as described in general process (C), or they may be prepared from the corresponding carboxyUc acid of formulae (VT) and (VII), respectively, by first being converted into the corresponding acyl halide by reaction with, for example, oxalyl chloride. The acyl halide is then converted into the corresponding acyl azide by reaction with, for example, with sodium azide. The desired isocyanate is then obtained by a conventional Curtius rearrangement by heating the acyl azide at reflux. The reactions are conveniently effected in a
suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane.
Compounds of formula (III) and (TV) in which X is a sulfur atom may be prepared from the corresponding amine of formula (IV) and (II), respectively 5 (wherein R8 and R4 are hydrogen), by reaction with l,l'-thiocarbonyl-2(lH)- pyridone. The reaction is conveniently effected at room temperature in a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane.
Compounds of formulae (II) to (Nil) are either known compounds or may be prepared by conventional methodology well known to one of ordinary skill in 10 the art using, for instance, procedures described in the accompanying Examples, or by alternative procedures which will be readily apparent.
For example, compounds of formula II in which B is a nitrogen atom and A, D and E are carbon atoms, one group R2 is present at the 3 -position and R3 is hydrogen, can be made by reacting a compound in which the amino group is lδ absent with a mixture of concentrated sulfuric acid and fuming nitric acid at about 0°C for about 30 minutes followed by reduction of the resultant nitro group for example using hydrogen and Lindlar catalyst, in a solvent such as methanol.
This compound can be made by reacting a compound of formula VIII:
20 (VIII)
in which R1 is as defined above with ammonia, generally at about 80°C for about δ hours, at a pressure of about 3δ psi in a Parr apparatus.
The compound of formula VIII can be made by successively reacting a 2δ compound of formula IX:
in which R1 is as defined above with a carbonylating agent such as dichloromethyl methylether in a solvent such as dichloromethane in the presence δ of a catalyst such as titanium tetrachloride at about room temperature for about an hour. The methoxy group is converted to a hydroxy group using a reagent such as borontribromide in a solvent such as dichloromethane at about room temperature for several hours. This compound is optionally activated, for example by forming the trifluoromethylsulfonate using trifluoromethanesulfonic 10 anhydride generally in the presence of a base such as triethylamine and a solvent such as dichloromethane for about one hour at room temperature. This compound is reacted with a solution of a compound of formula X:
R
(X) lδ in which R2 is as defined above, which solvent is generally DMF, in the presence of a base such as triethylamine and preferably catalysts such as dichlorodi(triphenylphosphine)paIladium at about room temperature for two to four hours. An alternative activation can also occur by making the bromide in
20 place of the trifluoromethane sulfonate.
The carbonyl moiety in the compounds of formula VIII can also be produced by selectively reducing a carboxylic acid moiety using a reagent such as borane tetrahydrofuran complex in tetrahydrofuran, at about room temperature for about 4 hours, to the alcohol followed by selective oxidation to the aldehyde
2δ using, for example, oxalyl chloride in DMSO in a solvent such as dichloromethane at about room temperature for about an hour.
Compounds of formula II in which one group R2 is present at the 3-position, B is nitrogen and A, D and E are carbon can also be made by reacting a compound of formula (XI):
(XI)
in which R1 is as defined above, with the acetal of a compound of formula H2NCHR2CHO, in which R2 is as defined above, generally at reflux for about 2 hours under Dean/Stark conditions followed by the addition of an acid such as concentrated sulfuric acid at a temperature of about 140°C for about 30 minutes.
Compounds of formula II in which an alkyl group is present at the 1- position can be made by the following sequence. A compound of formula (XII):
in which R1 and R2 are as defined above, is reacted with an alkylating agent, such as the appropriate Grignard reagent, generally in a solvent such as tetrahydrofuran for several hours at about room temperature followed by ehmination of water under acidic conditions, to produce the corresponding indene. This is converted to the corresponding epoxide, for example using ozone at a temperature of about -78°C for about 9% hours. This is followed by reacting with ammonium hydroxide at about room temperature for about 2 days to produce the isoquinoline which is then nitrated and reduced to produce the amine.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W.
McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:
The structures of the products of the following Descriptions and Examples were in most cases confirmed by Η NMR.
Description 1
2- Cyano- δ -(trifluoromethvDp yridine
To an ice-cooled solution of δ-(trifluoromethyl)pyridin-2-ol (10.24 g, 62.8 mmol) in anhydrous dichloromethane (200 ml) was added triethylamine (9.63 ml , 69 mmol), followed by dropwise addition of trifluoromethanesulfonic anhydride (12.68 ml , 7δ.4 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with water (600 ml) and the aqueous layer extracted with dichloromethane (2 x 100 ml). The combined organic layers were washed with water (2 x 300 ml), brine (lδO ml), then dried over Na2SO4, filtered through a 1 inch plug of silica gel and evaporated. The residue was dissolved in anhydrous N,N-dimethylformamide (150 ml) and zinc cyanide (3.98 g, 33.9 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (Pd(PPli3)4) (3.56 g, 3.09 mmol). The mixture was degassed and heated at 80 °C overnight. The cooled reaction mixture was diluted with water (600 ml) and extracted with ethyl acetate (3 x 150 ml). The combined organic layers were washed with water (2 x 250 ml), brine (150 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on sihca eluting with a gradient rising from neat iso-hexanes to 10% Et2θ in iso-hexanes to give the title compound (8 g, 7δ%) as a white solid.
Description 2
2-Aminomethyl-5-(trifluoromethyl.pyridine
To a nitrogen flushed solution of 2-cyano-5-(trifluoromethyl)pyridine (Description
1; 8.0 g, 46.δmmol) in a mixture of ethanol (100 ml) and ammonium hydroxide
(2δ ml) was added a spatula end of Raney Nickel and the resulting mixture hydrogenated at 60 psi overnight. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient rising from 2% MeOH in δ dichloromethane + 0.5% NH4OH to 5% MeOH in dichloromethane + 0.5% NH4OH to give the title compound (2.5 g, 30%) as a yellow oil.
Description 3
0 To a solution of 4-teri-butylpyridine (44.3 ml, 300 mmol) in glacial acetic acid (200 ml) was added hydrogen peroxide (37.1 ml of a 27.5 % aqueous solution, 300 mmol), and the resulting mixture heated at reflux overnight. The cooled mixture was evaporated to dryness. The residue was dissolved in dichloromethane (200 ml), and washed with brine (50 ml), then dried (Na SO ) 5 and evaporated to give the title compound (40 g, 88%) as a white solid.
Description 4
2- Cyano-4- tert-butylp yridine
To trimethylsilylcyanide (2δ.O ml, 187.δ mmol) was added a solution of 4-tert- 0 butylpyridine-N-oxide (Description 3; 22.68 g, lδO mmol) in anhydrous dichloromethane (200 ml). To this mixture was added dropwise a solution of dimethyl carbamoyl chloride (17.26 ml, 187.6 mmol) in anhydrous dichloromethane (δO ml). The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous K2CO3 (200 ml) was added dropwise and δ the resulting mixture stirred for 10 minutes. The organic layer was separated and the aqueous layer extracted with 2 further portions of dichloromethane (100 ml). The combined organic layers were dried (Na2SO4) and evaporated to give the title compound (24 g, 100%).
0 Description 5
2-Aminomethyl-4-tert-butylpyridine
A solution of 2-cyano-4-tert-butylpyridine (Description 4; 24.0 g, lδO mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was taken up in dichloromethane (300 ml) and washed with
brine, dried over K2CO3, filtered and evaporated. The residue was purified by column chromatography on silica eluting with δ% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (12 g, 48%) as a pale yellow oil.
δ Description 6
2- |"4-(Trifluoromethyl)phenyll ethylamine
A solution of [4-(trifluoromethyl)phenyl]acetonitrile (9.98 g, δ3.9mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was purified by column chromatography on sihca eluting 0 with 4% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (6.δ g, 63%) as an orange oil.
Description 7
3-ter£-Butylphenyl trifluoromethane sulfonate 5 To an ice-cooled solution of 3-tert-butylphenol (10 g, 66.6 mmol) and triethylamine (13.92 ml, 99.9 mmol) in anhydrous dichloromethane (100 ml) under an atmosphere of nitrogen was added slowly trifluoromethanesulfonic anhydride (12.30 ml, 73.26 mmol), and the resulting mixture stirred at room temperature for 2 hours. The mixture was then washed with IN HCl (100 ml), 0 brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with iso-hexanes to give the title compound (16.38 g, 87%) as a clear oil.
Description 8
To a solution of 3-teri-butylphenyl trifluoromethane sulfonate (Description 7; 16.37 g, 58 mmol) in anhydrous N,N-dimethylformamide (200 ml) was added zinc cyanide (8.17 g, 69.6 mmol), and Pd(PPli3)4 (3.3δ g, 2.9 mmol) and the mixture was then degassed (N2) and heated at 80 °C overnight. The cooled reaction 0 mixture was poured into water (7δ0 ml), and extracted with ethyl acetate
(3 x 200 ml). The combined organic layers were washed with water (2 x 300 ml), brine (200 ml), dried (Na2SO4), filtered through a 1 cm plug of silica and evaporated to give the title compound (7 g, 76%).
Description 9
3-tert-Butylbenzylamine
A solution of 3-terf-butylbenzonitrile (Description 8; 7.0 g, 44 mmol) was hydrogenated according to the method of Description 2. Following removal of the δ catalyst, the residue was taken up in dichloromethane (100 ml), washed with brine, dried (Na2SO4), filtered through a short plug of sihca and evaporated to give the title compound (δ.2 g, 72%) as a red oil.
Description 10
10 2-tert-Butyl-δ-cvanopyridine
To a mixture of 3-cyanopyridine (10 g, 96 mmol), trimethylacetic acid (9.8 g, 96 mmol) and silver nitrate (1.63 g, 9.6 mmol) in 10% aqueous sulfuric acid (100 ml) at 70°C was added dropwise a solution of ammonium peroxodisulfate (21.9 g, 96 mmol) in water (120 ml). After complete addition the mixture was lδ stirred at 70°C for 2 hours. The mixture was cooled and basified by the addition of 33% aqueous NH4OH, and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried (Na2SO4) and evaporated to give the title compound (lδ.6 g, 100%).
20 Description 11
3-Aminomethyl-6-tert butylpyridine
A solution of 2-tert-butyl-δ-cyanopyridine (Description 10; lδ.δ g, 97 mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was purified by column chromatography on sihca eluting 2δ with δ% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (10.5 g, 66%), as a pale yellow oil.
Description 12
2-tert-Butyl-4-cvanopyridine 30 A mixture of 4-cyanopyridine (10 g , 96 mmol), trimethylacetic acid (9.8 g,
96 mmol), and silver nitrate (1.63 g , 9.6 mmol) in 10% aqueous sulfuric acid (100 ml) at 70°C was treated with a solution of ammonium peroxodisulfate (21.9 g, 96 mmol) in water (120 ml) according to the method of Description 10.
Purification by column chromatography on silica eluting with 10% Et2O in iso-hexanes gave the title compound (6.δ g, 42%).
Description 13 δ 4- Aminomethyl- 2- tert-butylp yridine
A solution of 2-tert-butyl-4-cyanopyridine (Description 12; 6.δ0 g, 40.6 mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was taken up in dichloromethane (100 ml), washed with brine, dried (Na2SO4), filtered through a short plug of silica and evaporated to 10 give the title compound (6.1 g, 91%) as a brown oil.
Description 14
2-Bromo-6-tert-butylpyridine
To potassium tert-butoxide (1.0M in tert butanol, 100 ml, 100 mmol) was added lδ 2,6-dibromopyridine (lδ.87 g, 67 mmol), and the resulting mixture heated at reflux for 3.δ hours. The mixture was evaporated and the residue quenched by the addition of water (150 ml). The mixture was extracted with ethyl acetate (3 x 80 ml) and the combined organic layers washed with brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography
20 on silica eluting with 2% Et2O in iso-hexanes to give the title compound (9.9 g, 69%) as a clear oil.
Description 15
25 To a solution of 2-bromo-6-tert-butylpyridine (Description 14; 9.9 g, 46 mmol) in anhydrous N,N-dimethylformamide (130 ml) was added zinc cyanide (6.48 g, 5δ.2 mmol) and Pd(PPli3)4 (2.6δ g, 2.3 mmol). The mixture was degassed then heated at 80 °C overnight. The cooled reaction mixture was poured into water (δOO ml), and extracted with ethyl acetate (3 x lδO ml). The combined organic
30 layers were washed with water (2 x 300 ml), brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with δ% Et2θ in iso-hexanes to give the title compound (6.6 g, 89%).
Description 16
2-Aminomethyl-6-tert-butylpyridine
A solution of 2-tert-butyl-6-cyanopyridine (Description lδ, 6.6 g, 41.2 mmol) was hydrogenated according to the method of Description 2. Following removal of the δ catalyst, the residue was taken up into dichloromethane (300 ml) and washed with brine, dried over K2CO3, filtered and evaporated. The residue was purified by column chromatography on silica eluting with δ% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (4.δ g, 66%) as a pale orange oil.
10 Description 17
(E/ )-3-r6-(Trifluoromethyl)pyridin-3-yllprop-2-enenitrile
To an ice-bath cooled suspension of sodium hydride (1.26 g of a 60% dispersion, 31.46 mmol) in anhydrous THF (7δ ml) was added dropwise a solution of diethyl cyanomethylphosphonate (δ.09 ml, 31.46 mmol) in THF (δO ml). After the lδ addition was complete the mixture was stirred for 10 minutes then a solution of 6-(trifluoromethyl)pyridine-3-carboxaldehyde (δ.00 g, 28.6 mmol) in THF (2δ ml) was added and the resulting mixture stirred at room temperature for 1 hour. Water (2δ0 ml) was added and the mixture extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with water (x2), brine,
20 dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with a gradient rising from 10% ΕtOAc in isohexanes to 30% ΕtOAc in iso-hexanes to give the title compound - Ε and Z isomers were separated but then re-combined (δ.6 g, 100%).
2δ Description 18
3-r6-(Trifluoromethyl)pyridin-3-yllpropylamine
A solution of (E/Z)-3-[6-(trifluoromethyl)pyridin-3-yl]prop-2-enenitrile (Description 17; δ.60 g, 28.3mmol) was hydrogenated according to the method of Description 2. Following removal of the catalyst, the residue was purified by 30 column chromatography on silica eluting with δ% MeOH in dichloromethane + 0.6% NH4OH to give the title compound (3.δ g, δ7%).
Description 19
1.2.3.4-Tetrahvdronaphthalene-2-carboxamide
To a suspension of l,2,3,4-tetrahydronaphthalene-2-carboxylic acid (6.08 g, 34. δ mmol) in anhydrous dichloromethane (60 ml) was added oxalyl chloride δ (4.δ2 ml, 51.8 mmol), followed by 2 drops of N,N-dimethylformamide and the resulting mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness, toluene (50 ml) was then added and the mixture evaporated to dryness again. The residue was dissolved in anhydrous dichloromethane (100 ml) and added in one portion to dichloromethane (150 ml)
10 which had been saturated with ammonia gas. The resulting mixture was stirred at room temperature for 48 hours. The mixture was evaporated to dryness and the residue partitioned between ethyl acetate (150 ml) and water (250 ml). The aqueous layer was further extracted with ethyl acetate (100 ml). The combined organic layers were washed with water (200 ml), brine (100 ml), then dried lδ (Na2SO4) and evaporated to give the title compound (6 g, 99%) as a white solid.
Description 20
1.2.3.4-Tetrahydronaphthalen-2-ylmethylamine
To an ice-bath cooled solution of l,2,3,4-tetrahydronaphthalene-2-carboxamide
20 (Description 19; δ.99 g, 34.2 mmol) in anhydrous THF (lδO ml) was added in portions lithium aluminum hydride (2.6 g, 68.4 mmol). After complete addition, the mixture was heated to reflux for 3 hours then cooled in an ice bath and quenched carefully by the sequential addition of water (2.74 ml), 4N NaOH (2.74 ml) and water (8.2 ml). The resulting suspension was stirred for 10
2δ minutes, then filtered through Celite™ and the itrate evaporated to give the title compound (4.δ g, 81%).
Description 21
.2E/ )-3-r4-(Trifluoromethyl)phenyllprop-2-enenitrile 30 To a solution of 4-trifluoromethyhodobenzene (7.23 g, 26.6 mmol) in anhydrous acetonitrile (130 ml) was added triethylamine (3.74 ml, 26.6 mmol), acrylonitrile (1.77 ml, 26.6 mmol), palladium (II) acetate (60 mg, 0.26 mmol), and tri-o- tolylphosphine (324 mg, 1.06 mmol) and the resulting mixture heated at reflux overnight. The cooled reaction mixture was filtered through Celite™, and
partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with δ% EtOAc in iso-hexanes to give the title compound (4.07 g, 78%). δ
Description 22 3-f4-(Trifluoromethyl)phenyllpropylamine
A solution of (2E/E)-3-[4-(trifluoromethyl)phenyl]prop-2-enenitrile (Description 21; 4.06 g, 20.6 mmol) was hydrogenated according to the method of 10 Description 2. Following removal of the catalyst, the residue was purified by column chromatography on silica eluting with 4% MeOH in dichloromethane + 0.δ% NH4OH to give the title compound (3.δ g, 83%) as an oil.
Description 23 lδ 3-[3-(Trifluoromethyl)phenyllpropylamine
To an ice-bath cooled suspension of sodium hydride (1.32 g of a 60% dispersion in oil, 33 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere was added dropwise a solution of diethyl cyanomethylphosphonate (δ.34 ml, 33 mmol) in tetrahydrofuran (40 ml) and the resulting mixture stirred
20 at 0 °C for lδ minutes. To this mixture was added a solution of
3-trifluoromethylbenzaldehyde (δ.22 g, 30 mmol) in anhydrous tetrahydrofuran (40 ml) and the resulting mixture stirred at room temperature for l.δ hours. Water (300 ml) was added and the mixture extracted with ethyl acetate (3 x lδO ml). The combined organic layers were washed with water (2 x 200 ml),
2δ brine (150 ml) then dried (Na2SO4) and evaporated. The residue was taken up in a mixture of ethanol (100 ml) and ammonium hydroxide (25 ml) and hydrogenated according to the method of Description 2. Purification by column chromatography on silica eluting with 5% MeOH in dichloromethane + 0.δ% NH4OH gave the title compound (l.δ g, 2δ%) as a yellow oil.
30
Description 24
6-(4-Fluorophenyl)nicotinamide
A mixture of 6-chloronicotinamide (δ.00 g, 31.9δ mmol), 4-fluorobenzene boronic acid (4.92 g, 3δ.l4 mmol), and Pd(PPh3)4 (1.10 g, 0.96 mmol) in a mixture of
toluene (80 ml), ethanol (12 ml) and 2M sodium carbonate (36.74 ml, 73.48 mmol) was degassed (N2) and heated at 100 °C for 18 hours. The reaction mixture was cooled to room temperature and then filtered. The collected solid was washed with water and dried. The dried solid was taken up in methanol (100 ml) and δ heated to reflux for 20 minutes. The mixture was then cooled to room temperature, filtered and the solid dried to give the title compound (6.2δ g, 90%) as a pale grey sohd.
Description 25
10 f6-(4-Fluorophenyl)pyridin-3-yllmethylamine
To an ice-bath cooled solution of sodium borohydride (δ.47 g, 144.6 mmol) in anhydrous 1,4-dioxane (100 ml) was added slowly a solution of glacial acetic acid (8.27 ml, 144.δ mmol) in 1,4-dioxane (50 ml). To this mixture was added 6-(4-fluorophenyl)nicotinamide (Description 24; 6.25 g , 28.9 mmol) and the lδ resulting mixture heated at reflux for 4 hours. The cooled reaction mixture was evaporated and water (60 ml) added slowly. This mixture was extracted with dichloromethane, and the sohd which appeared between the layers was removed by filtration. This sohd was triturated with a mixture of dichloromethane and iso-hexanes, filtered and dried to give the title compound (δlO mg, 8%) as a pale
20 green sohd.
Description 26
6.7.8.9-Tetrahvdro-δH-benzorαir71annulen-6-ylmethylamine hydrochloride
To a nitrogen flushed solution of methyl 6,7-dihydro-5H-benzo[α][7]annulene-8-
2δ carboxylate [J. Org. Chem. 1991, 56, 6199-6206] (δ4.8 g, 271 mmol) in a mixture of ethyl acetate (2δ0 ml) and glacial acetic acid (δ ml) was added 10% palladium on carbon (10 g) and the mixture was hydrogenated at δδ psi for 16 hours. The catalyst was removed by filtration, and the filtrate evaporated to dryness. The residue was dissolved in ethanol (δδ ml) and 3M aqueous NaOΗ (165 ml,
30 495 mmol) was added, then the resulting mixture heated to reflux for 2 hours. The mixture was cooled and the ethanol removed by evaporation. The aqueous phase was washed with dichloromethane (x 3) then acidified to pΗ=l with 6M HCl and extracted with dichloromethane (x 3). The combined organic phases from the acidic extraction were dried over MgSO4, filtered and evaporated. The
residue was triturated with tert-butyl methyl ether, filtered and dried to give 6,7,8,9-tetrahydro-δH-benzo[α][7]annulene-6-carboxylic acid (20.6 g, 40%). This material was dissolved in dichloromethane (100 ml) containing N,N-dimethylformamide (O.δ ml) and oxalyl chloride (9.68 ml, 111 mmol) δ dropwise at such a rate that the internal temperature did not rise above 10 °C. The mixture was stirred at δ °C for 30 minutes, then treated dropwise with 33% aqueous ammonium hydroxide (100 ml) whilst maintaining the temperature below lδ °C. The resulting slurry was then stirred at 10 °C for 30 minutes. The mixture was evaporated and the residue diluted with water and slurried at 0 °C
10 for lδ minutes. The resulting white solids were filtered, washed with more water, hexanes, and dried to give 6,7,8.9-tetrahydro-δH-benzo[α][7]annulene-6- carboxamide (11.6 g, δδ%). This material was dissolved in anhydrous TΗF and added dropwise over 60 minutes to a slurry of LiAlΗ4 (3.24 g, 8δ.4 mmol) in refluxing THF. The reaction was maintained at reflux for 2 hours then cooled to lδ 10 °C, diluted with tert-butyl methyl ether, and cautiously quenched by the addition of water while the temperature was maintained below 30 °C. The resulting gummy solid was removed by filtration and the phases were then separated. The aqueous phase was washed with teri-butyl methyl ether and the combined organic phases were dried over MgSO4, filtered and evaporated. The
20 residue was dissolved in isopropyl alcohol (30 ml), cooled to 0 °C and concentrated HCl was added dropwise causing a thick slurry to form. The slurry was concentrated and the residue reconstituted with tert-butyl methyl ether and stirred at 40 °C for lδ minutes. The mixture was cooled to 2δ °C, filtered and the resulting solids washed with tert-butyl methyl ether and dried to give the title
25 compound.
Description 27 7-(Nitromethyl)-6,7.8.9-tetrahvdro-5H-benzof ir71annulene A solution of 8,9-dihydro-5H-benzo[α][7]annulen-δ-one (323 g, 2 mol) in 30 nitromethane (620 ml) was treated with DBU (327 g, 2.1 mol) dropwise at such a rate that the temperature was maintained between 40 and δO °C. After GC analysis showed reaction completion, 3M ΗC1 (600 ml) was added and the resulting mixture was extracted with terf-butyl methyl ether (2 x 600 ml). The combined organic phases were treated with brine (600 ml), dried over MgSO4,
filtered and evaporated to an oil (496 g, 90%). To 347.5g (1.58 mol) of this material dissolved in TFA (104δ ml) was added triethylsilane (583 ml, 3.65 mol) at such a rate that the temperature of the reaction mixture was maintained between 50 and 55 °C. After the addition was complete, the mixture was 5 maintained at δδ °C until GC analysis indicated reaction complete. The mixture was poured onto ice (lδOO g) and water (600 ml). The resulting slurry was filtered and washed with cold hexanes (2 x lδO ml) then dried to give the title compound (139 g, 42%).
10 Description 28
6.7.8.9-Tetrahvdro-δH-benzorαir71annulen-7-ylmethylamine hydrochloride A mixture of 7-(nitromethyl)-6,7,8,9-tetrahydro-δH-benzo[ ] [7]annulene (Description 27; 48.6 g , 0.24 mol) and Ra-Ni (δO g) in ethanol (600 ml) was hydrogenated at 60 psi for 12 hours. An additional charge of Ra-Ni (δO g) was lδ added and the mixture was hydrogenated until GC analysis indicated the reaction was complete. The resulting mixture was filtered over Celite™ and washed with ethanol (200 ml). The filtrate was treated with concentrated ΗC1 (3δ ml, 0.42 mol) and concentrated under reduced pressure. The product was then slurried in teri-butyl methyl ether (100 ml) and cooled between 0 and δ°C,
20 filtered and washed with terϊ-butyl methyl ether (100 ml) and dried to give the title compound (21 g, 42%).
Description 29
3-(lH-Pyrazol- l-yl)benzylamine hydrochloride
2δ To a suspension of 3-(lH-pyrazol-l-yl)-benzoic acid [see WO 00/219δl] (104 g, O.δδ mol) in anhydrous benzene (δOO ml) was added thionyl chloride (8δ g, 0.71δ mol) and DMF (O.δ ml). The mixture was heated at reflux for 3 hours, then evaporated under reduced pressure. The residue was dissolved in anhydrous TΗF (100ml) and evaporated. The residue was dissolved in anhydrous acetone
30 (600 ml), and treated with ammonium acetate (77 g, 1 mol). The mixture was heated at reflux for 12 hours, solvent was evaporated and the residue treated with cold water (2000 ml). The resulting precipitate was filtered, washed with cold water (200ml) and recrystallised from absolute ethanol (600 ml) to give 3-(lH-pyrazol-l-yl)benzamide (82 g, 80 %). A solution of this material (82 g,
0.44 mol) in THF was added dropwise to a solution of LiAffl (25 g, 0.66 mol) in anhydrous THF (800 ml). The mixture was heated at reflux for 4 hours, cooled and quenched by the sequential addition of water (25 ml), 15% aqueous NaOH (25 ml), and water (50 ml). The inorganic by-products were filtered off and δ washed several times with diethyl ether (overall volume 1000 ml). The combined filtrates were dried over Na2SO , filtered and evaporated. The residue was dissolved in methanol (400 ml), the solution was treated with activated carbon (10 g), and the mixture was re-fluxed for 40 minutes, then filtered and evaporated. The residue was treated with IN HCl in ether (1000 ml), and the precipitate 10 formed was filtered, washed with ether and dried to give the title compound (63 g, 70%).
Description 30
4-(lH-Pyrazol- l-yl)benzylamine hydrochloride lδ The title compound was prepared from 4-(lH-pyrazol-l-yl) -benzoic acid in an analogous procedure to that detailed in Description 29.
Description 31
N-Methyl-N- T4- (trifluor omethyDbenzyll amine
20 A mixture of 4-(trifluoromethyl)benzylamine (1.0 mL, 7.02 mmol) and di-tert- butyl carbonate (1.68 g, 7.72 mmol) in CΗ2CI2 (10 mL) was stirred for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution, extracted with CH2CI2 and the organic layers were combined, dried over MgSO4 and concentrated in vacuo to give a white crystalline sohd. To a solution
26 of the crude carbamate (1.00 g, 3.61 mmol) in THF (20 mL) in a room temperature water bath, was added LiAlH4 (0.69 g, 18.1 mmol) portion- wise over 10 minutes. The reaction was then heated at reflux for 4 hours. The reaction was cooled in ice and quenched by the addition of water (1.6 mL) and NaOH (2N, 1.3 mL). The grey slurry was filtered and washed with MeOH. The MeOH was
30 removed in vacuo and the crude product taken up in CH2CI2 and dried over
MgSO4 and concentrated in vacuo. Purification by flash column chromatography eluting with δ-10 % MeOH in CH2Cl2plus 1 % NHs solution (2Nin MeOH) afforded the title compound.
Description 32 l-[4-(Trifluoromethyl)phenyl]ethylamine
To a suspension of NaCNBH4 (0.48 g, 7.6 mmol) and 3A molecular sieves (4 g) in MeOH (lδ mL) was added NH4OAc (6.16 g, 80 mmol) and 5 4- (trifluoromethyl) acetophenone (l.δ g, 8.0 mmol). The reaction was stirred at room temperature under nitrogen for 3 days. The reaction was concentrated in vacuo and the pH adjusted to pH 12 by the addition of aqueous NaOH (2N). The reaction was extracted with ethyl acetate and the organic layers combined, dried over MgSO4 and the solvent removed in vacuo. Purification by flash column 10 chromatography, eluting with 5 % MeOH in CH2CI2 afforded the title compound.
Description 33
1.3-Diphenylpropylamine
The title compound was prepared from 1,3-diphenylpropan-l-one in an analogous lδ procedure to that detailed in Description 32.
Description 34
(3-Phenyl-1.2.4-oxadiazol-5-yl)methylamine hydrochloride
A mixture of δ-chloromethyl-3-phenyl- 1,2, 4-oxadiazole [Synth. Commun. 1992,
20 22, 209] (90 g, O.δ mol) and potassium iodide (45 g) was added as one portion to a suspension of potassium phthalimide (90 g, 0.5 mol) in DMSO (400 ml) under intensive stirring. After self-heating ceased, the mixture was heated at 130 °C for lδ minutes, cooled, and poured into water (2.δ 1). The precipitate was filtered, washed with water, and dried in the air. Recrystallization from δ% DMSO in
25 ethanol (1 1) afforded 100 g of sohd. A suspension of this sohd (100 g, 0.33 mol) in ethanol (2 1) was treated with glyme (0.5 1), heated to 35-40 °C, treated with hydrazine hydrate (18 g, 0.35 mol), and heated to reflux for 2 hours. The mixture was diluted with concentrated hydrochloric acid (100 ml), and refluxed for 4 hours. After cooling the mixture was filtered, extracted with ether, and
30 evaporated. The residue was dissolved in the minimum volume of water, basified and taken up in ether (300 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated. The residue was dissolved in the minimum volume of water, neutralized with hydrochloric acid and evaporated.
The crude product was recrystalhzed twice from isopropanol and dried to give the title compound (21 g, 20%).
Description 35
(2-Benzyl- 1.3-thiazol-4-yl)methylamine
2-Benzyl-4-chloromethylthiazole [Pharmazie 1972, 27, 146] (223.7 g, 1 mol) was stirred with hquid ammonia (600 ml) in an autoclave for 24 hours. The ammonia was removed and the product was distilled in vacuo [bp (0.02 mmHg) 141-144°C] to give the title compound (102 g, 60%). 0
Description 36
[1 - (2-Methylphenyl) - lH-p yr azol-4- yll methylamine
A mixture of l-(2-tolyl)-pyrazole-4-carboxaldehyde [see US Patent No. 4,220,792]
(186 g, 1 mol), hydroxylamine hydrochloride (104.2 g, 1.5 mol), and sodium 5 acetate trihydrate (204 g) in ethanol (2 1) was refluxed for 1 hour. The mixture was cooled, diluted with water (8 1), and left overnight. The precipitate was filtered to give l-(2-tolyl)-pyrazole oxime (186 g , 92.5 %). Tolylpyrazole oxime (60.3 g, 0.25 mol) in methanol (600 ml) and ammonia (200 ml) was hydrogenated in an autoclave in the presence of Raney nickel (10 g of ethanolic suspension) at 0 50°C at 70 atm. The catalyst was filtered off and washed with methanol. The filtrate was evaporated, and the residue was distilled in vacuo to give the title compound (43 g, 92%).
Description 37 δ 3-Cvclohexylpropylamine hydrochloride
To a solution of 3-phenyl-l-propylamine (5.26 ml, 0.04 mol) in ethanol (100 ml) under nitrogen was added concentrated ΗC1 (3 ml) and platinum oxide (0.5 g, 0.002 mol). This was placed on a Parr apparatus and hydrogenated at 60 psi for δ days. Platinum oxide (O.δ g, 0.002 mol) was added and the mixture 0 hydrogenated for a further 5 days. The mixture was filtered and evaporated to give the title compound (6.4 g , 98%).
Description 38
6.7.8.9-Tetrahvdro-5H-benzorαl [71annulene-7-carboxyhc acid A solution of 7-(nitromethyl)-6,7,8,9-tetrahydro-δH-benzo[ ][7]annulene (Description 27; 96 g, 0.47 mol) in TΗF (560 ml) was cooled to -18 °C and 5 potassium tert-butoxide (1.6M in TΗF, 263 ml, 0.42 mol) was added dropwise over 30 minutes while maintaining the temperature between -lδ and -δ°C. After stirring for 10 minutes a solution of KMnO4 (111 g, 0.7 mol) in water (900 ml) was added dropwise over 75 minutes while maintaining the temperature between -3 and 3 °C. The mixture was stirred at 0 °C until GC analysis indicated the 0 reaction was complete. terZ-Butyl methyl ether (500 ml) was added followed by saturated aqueous NaΗSOβ (1000 ml) and the resulting mixture was stirred for 30 minutes until a milky white slurry formed. This slurry was filtered, washed with a solution of 3N NaOΗ (50 ml) and water (100 ml) foUowed by tert-butyl methyl ether (100 ml). The pΗ of the filtrate was adjusted from 8.6 to 12.5 by the 5 addition of 3N NaOΗ (100 ml) and 6N NaOΗ (40 ml). The phases were separated and to the aqueous phase was added tert-butyl methyl ether (500 ml). The pΗ of the resulting mixture was adjusted to 2 with 6N ΗC1 (200 ml). The phases were again separated and the aqueous phase was extracted with terf-butyl methyl ether (2 x 300 ml). The organic phases were combined, dried over MgSO4, filtered 0 and evaporated to give the title compound (73 g, 89%), as an off white sohd.
Description 39
2-Bromo-6-fluorobenzaldehvde
To a solution of diisopropylamine (lδ.7 ml 112 mmol) in anhydrous δ tetrahydrofuran (200 ml) cooled to 0 °C was added dropwise n-butylhthium (2.6M in hexanes, 44.8 ml, 112 mmol). After complete addition the mixture was cooled to -78 °C and 3-fluorobromobenzene (19.6 g, 112 mmol) added over 10 minutes. The mixture stirred at -78 °C for 1 hour then N,N dimethylformamide (9.72 ml, 125 mmol) was added dropwise over 5 minutes. The mixture was stirred for a 0 further 10 minutes, then acetic acid (10 ml) and water (360 ml) were added. The mixture was allowed to warm to room temperature and was extracted with Et2θ (250 +150 ml). The combined extracts were washed with water (x2) 0.2N ΗC1, brine, dried over Na2SO4 and evaporated. The residue was purified by column
chromatography on sihca eluting with 5% Et2θ in iso-hexanes to give the title compound (20 g, 88%) as a white sohd.
Description 40 2-Fluoro-6-[(trimethylsilyl)ethynyllbenzaldehvde
To a solution of 2-bromo-6-fluorobenzaldehyde (Description 39; 10.0 g, 49.3 mmol) and (trimethylsilyl) acetylene (13.94 ml, 98.6 mmol) in anhydrous N,N-dimethylformamide (260 ml) under an atmosphere of nitrogen was added triethylamine (10.25 ml, 73.95 mmol), copper (I) iodide (0.94 g, 4.93 mmol) and Pd(PPli3)2Cl2 (1.73 g, 2.47 mmol). The mixture was degassed and stirred at room temperature overnight. The mixtiire was poured into water (600 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic layers were washed with water (3 x 300 ml), brine (200 ml) then dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5% Et2θ in iso-hexanes to give the title compound (10.38 g, 95%).
Description 41
8-Fluoroisoquinohne
2-Fluoro-6-[(trimethylsilyl)ethynyl]benzaldehyde (Description 40; 10.38 g, 47.1 mmol) was dissolved in 2M ammonia in methanol (235 ml, 471 mmol) in a Parr flask and the resulting mixture heated at 80 °C with shaking on a Parr apparatus (ca. 35 psi achieved). The reaction was cooled and the solvents evaporated. The residue was purified by column chromatography on silica eluting with a gradient from neat dichloromethane to 2% methanol in dichloromethane to give the title compound (4.0 g, 58 %).
Description 42
8-Fluoro-5-nitroisoquinohne
To a solution of 8-fluoroisoquinohne (Description 41; 1.24 g , 8.4mmol) in concentrated sulfuric acid (10 ml) cooled to between -5 °C and 0 °C was added slowly, over 10 minutes, a solution of potassium nitrate (0.93 g , 9.24 mmol) in concentrated sulfuric acid (5 ml). The mixture was stirred at 0 °C for 30 minutes after which time TLC indicated that reaction was complete. The mixture was poured onto ice (100 g) and basified by the careful addition of 33% aqueous
ammonium hydroxide. The mixture was extracted with dichloromethane (3 x 150 ml) and the combined organic layers were washed with brine, dried over Na2SO4 and filtered through a 1 inch plug of silica gel. The sihca gel plug was further washed with 150 ml of a 1:1 mix of ethyl acetate and iso-hexanes. The combined organics were evaporated to give the title compound (1.33 g, 82%) as a brown sohd.
Description 43
8-Fluoroisoαuinohn-5-amine To a nitrogen flushed solution of 8-fluoro-5-nitroisoquinohne (Description 42; 1.33 g, 6.9 mmol) in methanol (100 ml) was added 10% paUadium on carbon (500 mg) and the resulting mixture stirred under a balloon of hydrogen for 3.5 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was purified by MPLC (Biotage Flash™ 40) eluting with 2% MeOH in dichloromethane to give the title compound (450 mg, 40%) as a . yellow sohd.
Description 44
3-Methyl-5-nitroisoαuinoline 3-Methylisoquinoline (2.14 g, 14.9 mmol) was added portionwise to ice-cooled concentrated H2SO4 (10 ml) keeping the internal temperature below 10 °C. A nitrating mixture of concentrated H2SO4 (2 ml) and fuming nitric acid (2 ml) was then added dropwise keeping the internal temperature below 15 °C. After stirring for 30 minutes, TLC indicated reaction was complete. The acid was neutrahzed by adding the mixture to an excess of 4N aqueous NaOH (180 ml) with ice-cooling. The mixture was extracted with dichloromethane (2 x 150 ml), then dried (Na2SO4) and evaporated to give the crude product (2.69 g) as a yellow sohd. Flash column chromatography using as eluant 5% methanol in dichloromethane gave a pure sample of the title compound (660 mg) and a further sample (1.95 g) containing ca. 10% of the isomer 3-methyl-8-nitroisoquinohne.
Description 45
3-Methvhsoαuinohn-5-amine
3-Methyl-5-nitroisoquinoline (Description 44; 660 mg, 3.51 mmol) was dissolved in MeOH (30 ml) and Ptθ2 catalyst (120 mg) was added. The mixture was stirred for 1 hour 45 minutes under a balloon of hydrogen, then the catalyst was filtered off, washing with more methanol. The filtrate was evaporated and purified by flash column chromatography using as eluant 5% methanol in dichloromethane to give the title compound (250 mg).
Description 46
1-Chloroisoquinoline
A solution of isoquinoline-N-oxide (5.52 g, 38 mmol) in dichloromethane (60 ml) was added over 15 minutes to a solution of phosphorus oxychloride (40 ml) in dichloromethane (50 ml) at room temperature. The mixture was stirred for 1 hour, then heated to reflux for 2 hours. After coohng to room temperature, the mixture was poured into ice water (500 ml). The mixture was then extracted with dichloromethane (2 x 250 ml) and the combined organic layers were washed with 10% aqueous potassium carbonate solution (200 ml), brine (200 ml) then dried (Na2SO ) and evaporated to give the title compound (5.0 g).
Description 47 1-Chloro-δ-nitroisoquinoline
1-Chloroisoquinohne (Description 46; 4 g, 24.4 mmol) was nitrated according to the method of Description 44 to give the title compound (3.88 g).
Description 48 l-Chloroisoquinolin-5-amine
Copper (II) acetylacetonate (263 mg) was suspended in ethanol (10 ml) and sodium borohydride (366 mg) was added in one portion. The mixture was stirred for 5 minutes, by which time a black suspension had appeared. A suspension of 1-chloro-δ-nitroisoquinohne (Description 47; 1.01 g, 4.84 mmol) in ethanol (20 ml) was then added over 15 minutes whilst coohng in a water bath; the mixture effervesced. The mixture was stirred at room temperature for 1 hour, then more sodium borohydride (160 mg) was added and stirring continued for a further 1
hour. Water (100 ml) was added then the ethanol was evaporated and the mixture extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried (Na2SO4) and evaporated. Purification of the residue by flash column chromatography using 5% methanol-dichloromethane as eluant gave the title δ compound (210 mg).
Description 49
3 - Chloroisoquinoline
A mixture of 1,3-dichloroisoquinohne (9.94 g, 60.2 mmol) and hydrazine hydrate
10 (12.2 ml, 251 mmol) in ethanol (150 ml) was heated at reflux for 1.5 hours. The reaction was then cooled to room temperature and the ethanol evaporated. The residue was suspended in chloroform and manganese dioxide (20g) was added in portions over 30 minutes. Gas evolution was observed. After this had subsided, the mixture was heated to reflux for 2 hours, then filtered and evaporated. lδ Purification of the residue by flash column chromatography using dichloromethane as eluant gave the title compound (3.δ g).
Description 50
3-ChloroisoquinoHn-5-amine
20 3-Chloroisoquinoline (Description 49; 3.4 g, 20.7 mmol) was nitrated according to the method of Description 44 to give crude 3-chloro-δ-nitroisoquinohne (9 g). A sample (3.08 g) was added in portions over 15 minutes to a mixture of iron powder (4.2 g, 74 mmol) in water (50 ml) and 5M HCl (4 ml) at 50 °C. After the addition, the mixture was warmed to 85 °C for 2 hours, then filtered while still 5 warm to remove the iron. The filtrate was basified (4N NaOH, ca. 50 ml), then extracted with dichloromethane (3 x 150 ml). The combined organic layers were dried (Na2SO4) and evaporated to give the title compound (282 mg).
Description 51 0 6-Aminoisoquinoline
Benzophenone imine (445 μL, 2.64 mmol) was added to a mixture of 6-bromoisoquinohne (500 mg, 2.4 mmol), BINAP (60 mg, 0.1 mmol), palladium acetate (12 mg, 0.05 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in THF (10 ml) at room temperature. The mixture was degassed (N2 x 3) then heated at
reflux under a nitrogen atmosphere for 16 hours. The reaction was then cooled to room temperature, partitioned between ethyl acetate (20 ml) and water (20 ml) and the aqueous phase extracted with ethyl acetate (20 ml). The combined organic phases were evaporated then re-dissolved in THF (lδ ml). Hydrochloric δ acid (2N, aqueous, 4 ml) was added, then after stirring for 1 hour the THF was evaporated. The mixture was partitioned between ethyl acetate (20 ml) and 3M HCl (50 ml) and the aqueous phase washed with ethyl acetate (20 ml). The aqueous phase was basified (12N NaOH) then extracted with dichloromethane (3 x 50 ml). The combined organic phases were dried (Na2SO4) and evaporated to 0 give the title compound (360 mg).
Description 52 iV- (2-BromobenzvD - 2.2-diethoxyacetamide
To a solution of ethyl diethoxyacetate (20.0g, 114 mmol) in ethanol (50 ml) was 5 added a solution of sodium hydroxide (4.56 g, 114 mmol) in water (25 ml), and the resulting mixture heated at reflux for 5 hours. The mixture was evaporated to dryness, and the residue dried in vacuo. The resulting sohd (22.76 g, 0.13 mol) was dissolved in dry ether (88 ml) and to this mixtvire was added thionyl chloride (13.3 g, 0.11 mol) with stirring for 10 minutes at 10 °C. The reaction mixture was 0 heated at reflux for 30 minutes and then allowed to cool. A solution of
2-bromobenzylamine (20.73 g, 0.11 mol) in toluene (57 ml) and pyridine (34 ml) was poured into this reaction mixture with vigorous stirring. This was heated at reflux for 30 minutes and then allowed to cool. The mixture was poured into ice water and extracted with toluene (x 3). The organic extracts were combined and δ washed firstly with 2% HCl and then water. The solvent was evaporated and the residue purified by flash chromatography on sihca gel (9: 1 hexane:ethyl acetate) to give the title compound (lδ.6 g, 44%).
Description 53 0 8-Bromoisoquinolin-3-ol
N-(2-Bromobenzyl)-2,2-diethoxyacetamide (Description 52; 15.6 g , 49 mmol) was carefully added to concentrated H2SO4 (78 ml) with stirring at 10-20°C. The reaction mixture was stirred at room temperatxire for 16 hours, poured into ice water and filtered. The filtrate was neutralised with 33% aqueous ammonium
hydroxide and the resulting precipitate was filtered and dried to give the title compound (10.1 g, 91%).
Description 54 8-Bromo- 3 -methoxyisoquinohne
To a suspension of 8-bromoisoquinohn-3-ol (Description 53; 7.3 g, 0.03 mol) and silver carbonate (13.6 g, 0.05 mol) in dry DMF (380 ml) under nitrogen was added iodomethane (2.2δ ml, 0.04 mol). The mixture was stirred at 50 °C for 24 hours. Further iodomethane (1 ml, 0.015 mol) was added and the mixture heated for 64 hours at 50 °C. The mixture was cooled, water (300 ml) and ethyl acetate
(300 ml) were added and shaken well. The mixture was filtered through Celite™, the layers separated and the aqueous layer was extracted with ethyl acetate (3 x 50 ml). The organic layers were combined, evaporated to ~150 ml, washed twice with water and then brine. The organic extract was then evaporated to give the title compound (1.7 g, 22%).
Description 55
Methyl 3-methoxyisoquinohne-8-carboxylate
To a solution of 8-bromo-3-methoxyisoquinoline (Description 54; 1.6 g, 7.0 mmol) in anhydrous DMSO (12 ml) and methanol (8 ml) was added triethylamine (1.0 ml, 7.0 mmol), palladium acetate (30 mg, 0.1 mmol) and l,l'-bis(diphenylphosphine)ferrocene (7δ mg, 0.1 mmol). Carbon monoxide was bubbled through the mixture for 3 minutes and the reaction was then heated with stirring at 80 °C for 44 hours under a balloon of carbon monoxide. Palladium acetate (30 mg, 0.1 mmol), l,l'-bis(diphenylphosphine)ferrocene
(75 mg, 0.1 mmol), DMSO (4 ml) and methanol (6 ml) were added to the mixture and carbon monoxide was bubbled through for 3 minutes. The reaction was again heated at 80 °C under a carbon monoxide balloon for 5 hours. The mixture was aUowed to cool, brine (80 ml) was added and the mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine (50 ml), dried over K2CO3 and evaporated. The residue was chromatographed on sihca gel (19:1 dichloromethane: methanol) to give the title compound (290 mg, 20%).
Description 56
3-Methoxyisoquinohne-8-carboxyhc acid
To a solution of methyl-3-methoxyisoquinoline-8-carboxylate (Description 55; 280 mg, 1 mmol) in ethanol (10 ml) was added potassium hydroxide (145 mg, 3 mmol) in water (6 ml). This mixture was heated at reflux for 30 minutes, cooled and the ethanol removed by evaporation. The remaining aqueous mixture was acidified with IM HCl (3 ml) to pH δ. The sohd was collected by filtration and dried in a vacuum oven to give the title compound (23δ mg, 90%).
Description 57
Isoquinoline-8-carboxylic acid
THF (140 ml) was added to n-butylhthium (1.6M hexanes, 70 ml, 112 mmol) at -78 °C. A cold (-78 °C) solution of 8-bromoisoquinoline (19g, 91.3 mmol) was then added. The reaction was stirred for 15 minutes at -78 °C, then dry CO2 gas was bubbled through the solution for 30 minutes. The cooling was then removed and the mixture warmed to 0 °C over 1 hour. The THF was removed in vacuo, then aqueous NaOH (2N, 300 ml) was added. The mixture was washed with tert-butyl methyl ether (300 ml, then 2 x 100 ml) and the combined organic layers were back extracted with aqueous NaOH (2N, 50 ml). The combined aqueous phase was adjusted to pH 4.5 by the addition of 6N HCl. And the slurry cooled to 15 °C using an ice-bath. The precipitate was collected by filtration, washed with water (2 x 100 ml), isopropanol (100 ml), acetone (100 ml) and tert-butyl methyl ether (100 ml) to give the title compound (8.62 g).
Description 58
[4- (TrifluoromethyDbenzyll isocyanate
4-(Trifluoromethyl)phenylacetic acid (1.79 g, 8.77 mmol) was dissolved in dichloromethane (20 ml) at room temperature. Oxalyl chloride (0.92 ml, 10.5 mmol) was added foUowed by DMF (2 drops). The reaction was stirred for 4 hours, after which time effervescence had ceased. The dichloromethane and excess oxalyl chloride were then evaporated. The acid chloride was redissolved in DCM (20 ml) and poured in one go into a solution of sodium azide (0.63 g, 9.65 mmol) and tetrabutylammonium bromide (300 mg, 0.88 mmol) in water (15 ml). The mixture was stirred for 15 minutes, then the layers separated and the
aqueous layer extracted with more dichloromethane (30 ml). The combined organic layers were dried (Na2SO ) and evaporated to give an oil which was purified by flash column (50% dichloromethane-hexane). The acyl azide (1.54 g) so produced was dissolved in dichloromethane (20 ml) and heated at reflux to quantitatively afford the title compound. The volume was adjusted to give a 0.33 M solution in dichloromethane for use in subsequent preparations.
Description 59
[4-(Trifluoromethoxy)benzyllisocvanate Prepared from 4-(trifluoromethoxy)phenylacetic acid according to the method of Description 68.
Synthesis of Ureas:
Ureas were synthesized, unless otherwise stated, using one of 2 methods. A convenient procedure starts with a carboxyhc acid which, on treatment with diphenylphosphoryl azide and triethylamine, undergoes a Curtius reaction. The isocyanate formed in situ is then trapped by addition of an amine all in one-pot. Alternatively ureas are synthesized by reacting an amine with a preformed isocyanate. Urea precursors not mentioned in Descriptions 1 to 58 are known compounds.
Description 60
Representative one-pot procedure for the synthesis of ureas from a carboxyhc acid and an amine A mixture of carboxyhc acid (0.30 mmol), diphenylphosphoryl azide (65 μl,
0.30 mmol) and triethylamine (42 μl, 0.30 mmol) in toluene (5 ml) was heated at reflux for 1 hour. To this mixture, the appropriate amine (0.30 mmol) was added and the reaction heated at reflux for 18 hours. The cooled reaction mixture was evaporated to dryness, then purified either by flash column chromatography, preparative thin layer chromatography or by mass-directed HPLC. For amine hydrochloride salts, an extra equivalent of triethylamine was added.
Description 61
Representative one-pot procedure for the synthesis of ureas from an isocyanate and an amine
An amine (0.30 mmol) and an isocyanate (0.3δ mmol) were dissolved in dichloromethane (10 ml), then stirred at room temperature or at reflux if required until the starting amine had been consumed. The product was collected by filtration, washing with a httle dichloromethane. In cases where the product did not crystallise out, the solvent was evaporated and purification was effected either by flash column chromatography, preparative thin layer chromatography or by mass-directed HPLC.
Description 62
3 - (trifluoromethvDisoq uinohne l-Chloro-3-(trifluoromethyl)isoquinoline [see WO 01/92233 ] (2.0 g, 8.64 mmol) was dechlorinated according to the method of Description 49 to give the title compound (1.42 g).
Description 63
5-nitro-3-.trifluoromethyl)isoquinoline 3-(trifluoromethyl)isoquinoline (Description 62; 1 g, δ.O mmol) was nitrated according to the method of Description 44 to give the title compound (1.1 g).
Description 64
3-(trifluoromethyl)isoquinohn-5-amine 5-nitro-3-(trifluoromethyl)isoquinoline (Description 63; 1 g, 4.13 mmol) was hydrogenated according to the method of Description 43 to give the title compound (0.48 g).
Description 65 l-chloro-3-ethyl-5-nitroisoquinohne l-chloro-3-ethyhsoquinoline [see WO 01/92233] (2.0 g, 10.4 mmol) was nitrated according to the method of Description 42 to give the title compound (2.37 g, 96 %).
Description 66 l-chloro-3-ethvhsoquinohn-5-amine l-chloro-3-ethyl-5-nitroisoquinohne (Description 65; 2.0 g, 8.4 mmol) was reduced according to the method of Description 50 to give the title compound (1.2 g, 69 %).
Description 67 l-Methyl-5-nitroisoquinohne
Prepared by nitration of 1-methyhsoquinohne according to the procedure of
Description 44.
Description 68 l-Methyhsoquinohn-5-amine
Prepared by reduction of l-methyl-5-nitroisoquinohne (Description 67) according to the procedure of Description 45.
Description 69
2.4-Difluoro-6-methoxybenzaldehvde
To a solution of 3.5-difluoroanisole (26 g; 176 mmol) in dichloromethane (150 ml) cooled at 0°C was added titanium tetrachloride (30.7 ml; 280 mmol). To this mixture was added dropwise over 10 minutes dichloromethyl methylether (15.8 ml; 175 mmol), and after complete addition the mixture was stirred at room temperature for 1 hour. The reaction was poured onto ice/water (600 ml) and extracted with DCM (3 x 300 ml). The combined DCM layers were washed with water (600 ml), saturated NaCl (200 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on sihca - eluting with a gradient rising from 15% Et2θ in isohexanes rising to 30% Et2θ in isohexanes to give the title compound (11.2 g, 37%) as a white sohd.
Description 70 2.4-Difluoro-6-hvdroxybenzaldehyde
To a solution of 2,4-difluoro-6-methoxybenzaldehyde (Description 69, 11.2 g; 77.8 mmol) in anhydrous dichloromethane (600 ml) cooled at -78°C was added boron tribromide (9.47 ml; 85.68 mmol) dropwise over 10 minutes. After complete addition the mixture was allowed to warm to room temperature and stirred
overnight. The mixture was poured onto ice/water (1 htre) and extracted with DCM (3 x 400 ml). The combined organic layers were washed with water (1 htre), saturated NaCl (500 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica elution with 10% diethyl ether/ isohexanes to give the title compound (9.2 g, 75%) as an orange oil.
Description 71
2.4-Difluoro-6-prop- 1-ynylbenzaldehvde
To an ice-bath cooled mixture of 2,4-difluoro-6-hydroxybenzaldehyde (Description 70, 9.20 g; 58.2 mmol) and triethylamine (8.92 ml; 64.02 mmol) in anhydrous dichloromethane (100 ml) was added dropwise over 10 minutes trifluoromethanesulfonic anhydride (11.75 ml; 69.84 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water (300 ml), and the aqueous phase extracted with DCM (100 ml). The combined organic layers were washed with saturated NaCl (100 ml), dried over Na2SO4, filtered through a 1 inch plug of sihca and evaporated. The residue (14.4 g; 49.6 mmol) and triethylamine (10.37 ml; 74.4 mmol) in anhydrous N,N-dimethylformamide (80 ml) contained within a large (200 ml capacity) sealed tube was cooled to -78°C and propyne gas bubbled through until the volume had increased by approx 10 ml. To this mixture was added Pd(PPli3)2Cl2 (1.74 g; 2.48 mmol) and Cul (449 mg; 4.96 mmol), the hd was put in place and the tube allowed to reach room temperature. The reaction was stirred for 2 hours after which TLC showed reaction was complete. The mixture was poured onto water (500 ml) and extracted with EtOAc (3 x 150 ml); the combined EtOAc layers were washed with water (3 x 400 ml), saturated NaCl (150 ml), dried over Na2SO4, filtered through a 1 inch plug of sihca and evaporated to give the title compound (8.7g, 97%).
Description 72 6.8-Difluoro-3-methvhsoquinohne
A mixture of 2,4-difluoro-6-prop-l-ynylbenzaldehyde (Description 71, 8.7 g; 48.8 mmol) and 2.0M ammonia in methanol (244 ml; 488 mmol) were heated together at 80°C in a Parr apparatus (approx 35psi achieved) for δ hours. The cooled mixture was evaporated and the residue purified by column chromatography on
silica -elution with 100% dichloromethane to give the title compound (δ.2 g, 59%) as a brown sohd.
Description 73 6,8-Difluoro-3-methvhsoquinolin-5-amine To an ice-bath cooled solution of 6,8-difluoro-3-methyhsoquinoline (Description 72, 1.2 g; δ.35 mmol) in cone, sulfuric acid (7.6 ml) was added dropwise a mixture of fuming nitric acid (1 ml) and cone, sulfuric acid (1 ml) and the resulting mixture stirred at 0°C for 30 minutes. Poured onto ice/water (100 ml) and basified by the portionwise addition of NaHCOβ, then extracted with EtOAc (3 x 100 ml). The combined EtOAc layers were flushed with nitrogen and a spatula end of δ% palladium on carbon added and the reaction was stirred under a balloon of hydrogen for 3 hours. The catalyst was removed by filtration and the filtrate evaporated. The residue was purified by column chromatography on sihca elution with 1% MeOH in DCM + 0.6% NH4OH to give the title compound (930 mg, 89%).
Description 74
3-Methyl-7-(trifluoromethyl)isoquinohn-5-amine
Prepared using 2-hydroxy-5-trifluoromethylbenzaldehyde [see WO-A-9962902] in place of 2,4-difluoro-6-hydroxybenzaldehyde according to the procedures of Descriptions 71, 72, and 73 respectively.
Description 75
2-Fluoro-6-prop-l-vnylbenzaldehvde A mixture of 2-bromo-6-fluorobenzaldehyde [see Tetrahedron Letters (1992),
33(49), 7499-7502] (4.0 g; 19.7 mmol) and triethylamine (4.12 ml; 29.5 mmol) in anhydrous N,N-dimethylformamide (7δ ml) contained within a large (200 ml capacity) sealed tube was cooled to -78°C and propyne gas bubbled through until the volume had increased by approx 10 ml. To this mixture was added Pd(PPh3)2Cl2 (0.69 g; 0.99 mmol) and Cul (180 mg; 1.97 mmol), the hd was put in place and the tube allowed to reach room temperature and stir for 4 hours after which TLC showed the reaction was complete. The mixture was poured onto water (500 ml) and extracted with EtOAc (3 x 150 ml). The combined EtOAc layers were washed with water (3 x 400 ml), saturated NaCl (150 ml), dried over
Na2SO4, filtered through a 1 inch plug of sihca and evaporated to give the title compound (3.2 g, 100%).
Description 76
5 8-Fluoro-3-methvhsoquinohn-δ-amine
Prepared using 2-fluoro-6-prop-l-ynylbenzaldehyde (Description 7δ) in place of 2,4-difluoro-6-prop-l-ynylbenzaldehyde according to the procedures of Descriptions 72 and 73 respectively.
10 Description 77
(2-Bromo-4-fluorophenyl)methanol
To a solution of 2-bromo-4-fluorobenzoic acid (20g; 91mmol) in anhydrous THF (300 ml) at -10°C was added dropwise borane tetrahydrofuran complex (l.OM soln in THF) (136.5ml; 136.5mmol). After complete addition the reaction was allowed lδ to stir at room temperature for 4 hours. The reaction was quenched by the dropwise addition of water (20 ml). To the mixture was added saturated K2CO3 (200 ml) and water (300 ml). The organic layer was separated and the aqueous extracted with Et2O (2 x 300 ml). The combined organics were washed with water (2 x 500 ml), saturated NaCl (200 ml), dried over Na2SO4, filtered and
20 evaporated to give the title compound (18g, 96%) as a white sohd.
Description 78
2-Bromo-4-fluorobenzaldehvde
To a -78°C cooled solution of oxalyl chloride (8.43 ml; 96.58 mmol) in anhydrous
25 dichloromethane (300 ml) was added dropwise dimethyl sulfoxide (13.71 ml;
193.16 mmol). The mixture was stirred at -78°C for 5 minutes then a solution of (2-bromo-4-fluorophenyl)methanol (Description 77, 18 g; 87.8 mmol) in anhydrous dichloromethane (160 ml) was added slowly. The resulting mixture was stirred at -78°C for 15 minutes then triethylamine (36.71 ml; 263.4 mmol) was added and
30 the mixture allowed to warm to room temperature over 1 hour. The mixture was washed with water (2 x 500 ml), saturated NaCl (200 ml), dried over Na2SO4, filtered through a 2 inch plug of sihca gel and evaporated to give the title compound (16 g, 89%) as a white sohd.
Description 79
6-Fluoro-3-methvhsoquinolin-δ-amine
Prepared using 2-bromo-4-fluorobenzaldehyde (Description 78) in place of 2-bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 75, 72, and 73 respectively.
Description 80
2-Hvdroxy-δ-methoxy-3-nitrobenzaldehvde To a solution of 5-methoxysahcylaldehyde (22.62 g ; 148 mmol) in acetic acid (120 ml) was added dropwise over 1 hour a mixture of fuming nitric acid (7.1 ml) in acetic acid (25 ml). After complete addition the mixture was stirred at room temperature for 5 hours. The precipitate was removed by filtration, washed with ethanol and dried to give the title compound (20.3 g, 69%) as a bright yellow sohd.
Description 81
2-Formyl-4-methoxy-6-nitrophenyl trifluoromethanesulfonate
To an ice-bath cooled solution of 2-hydroxy-δ-methoxy-3-nitrobenzaldehyde (Description 80, 11.00 g; δδ.8 mmol) and triethylamine (10.11 ml; 72.54 mmol) in anhydrous dichloromethane (150 ml) was added slowly trifluoromethane sulfonic anhydride (11.73 ml ; 69.75 mmol) and the resulting mixture stirred at room temperature for 1.5 hours. The mixture was washed with water (250 ml), dried over Na2SO4, filtered through a 1.5 inch plug of sihca and evaporated to give the title compound (17 g, 92%) as a yellow oil.
Description 82
7-Methoxyisoquinohn-5-amine
Prepared using 2-formyl-4-methoxy-6-nitrophenyl trifluoromethanesulfonate (Description 81) in place of 2-bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 40, 41, and 43 respectively.
Description 83
1.3-Dimethvhsoquinohn-5-amine
Prepared using 1,3-dimethyhsoquinohne (Chem Lett. 1983, 5, 791) in place of 3- methyhsoquinohne according to the procedures of Descriptions 44 and 43 5 respectively.
Description 84
4-Chloro-2-formyl-6-nitrophenyl trifluoromethanesulfonate
10 Prepared using 5-chlorosahcylaldehyde in place of 5-methoxysalicylaldehyde according to the procedures of Descriptions 80 and 81 respectively.
Description 85
7-Chloro-3-methyl-5-nitroisoquinohne lδ Prepared using 4-chloro-2-formyl-6-nitrophenyl trifluoromethanesulfonate (Description 84) in place of 2-bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 76 and 72 respectively.
Description 86
20 7-Chloro-3-methyhsoquinolin-5-amine
To a nitrogen flushed solution of 7-chloro-3-methyl-δ-nitroisoquinohne (Description 85; 300 mg, 1.35 mmol) in methanol (30 ml) was added a spatula end of Palladium 5% on calcium carbonate poisoned with lead (Lindlar catalyst), and the resulting mixture stirred under a baUoon of hydrogen overnight. The catalyst
26 was removed by filtration and the filtrate evaporated. The residue was dissolved in methanol (20 ml) and sihca gel (2 g) added and evaporated to dryness. Loaded onto a sihca gel column and eluted with 1% MeOH in DCM + 0.5% NH4OH to give the title compound (190 mg , 73%) as an orange sohd.
30 Description 87
7-Chloroisoquinohn-5-amine
Prepared using 4-chloro-2-formyl-6-nitrophenyl trifluoromethanesulfonate (Description 84) in place of 2-bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 40, 41 and 86 respectively.
Description 88
8-Fluoro-3-methoxyisoquinohne-δ-carboxyhc acid
Prepared using 5-bromo-2-fluorobenzylamine in place of 2-bromobenzylamine according to the procedures of Descriptions 52, 53, 64, 56, and 56 respectively.
Description 89
6-Fluoroisoquinohn-5-amine
Prepared using 2-bromo-4-fluorobenzaldehyde (Description 78) in place of 2- bromo-6-fluorobenzaldehyde according to the procedures of Descriptions 40, 41, 44 and 43 respectively.
Description 90
7-Fluoroisoquinohn-5-amine Prepared using 2-bromo-5-fluorobenzoic acid in place of 2-bromo-4-fluorobenzoic acid according to the procedures of Descriptions 77, 78, 40, 41, 44 and 43 respectively.
Description 91 4-Methvhsoquinohn-5-amine
Prepared using 4-methyhsoquinoline (Tet. Lett. 1987, 28(44), 5291) in place of 3- methyhsoquinoline according to the procedures of Descriptions 44 and 43 respectively.
Description 92
8-(Trifluoromethyl)isoquinoline
A mixture of 2-trifluoromethylbenzaldehyde (15 g; 86 mmol) and aminoacetaldehyde dimethylacetal (9.37 ml; 86mmol) in toluene (75 ml) was heated at reflux under Dean/Stark conditions for 2 hours. The cooled reaction mixture was evaporated to dryness and the residue added dropwise to cone, sulfuric acid (200 ml) at 140°C ; after complete addition the heating was continued for 30 mins then the warm mixture was poured over ice. The mixture was filtered and the filtrate basified by the addition of 4N NaOH with cooling. The basic solution was extracted with Et2O (x 3), the combined Et2O layers were
dried over Na2SO4 , filtered and evaporated. The residue was dissolved in DCM and filtered through a short plug of sihca and evaporated to give 1.2g (Yield 7%).
Description 93 δ 8-(Trifluoromethyl)isoqυinohn-δ-amine
Prepared using 8-(trifluoromethyl)isoquinoline (Description 92) in place of 3- methylisoquinoline according to the procedures of Descriptions 44 and 43 respectively.
0 Description 94
2-Methoxy-4-(trifluoromethyl)benzonitrile
To a solution of 2-nitro-4-(trifluoromethyl)benzonitrile (22.48 g, 104 mmol) in anhydrous methanol (110 ml) was added dropwise 25% sodium methoxide in methanol (24.72 ml, 114.4 mmol), and the resulting mixture stirred at room 5 temperature for 1 hour. Water (110 ml) was added and the resulting sohds coUected by filtration. The sohds were dissolved in DCM (150 ml), washed with sat NaCl (75 ml), dried over Na2SO4, filtered and evaporated to give the title compound (19 g, 91%) as a white sohd.
0 Description 95
2-Methoxy-4-(trifluoromethyl)benzoic acid
To a solution of 2-methoxy-4-(trifluoromethyl)benzonitrile (Description 94; 19 g, 94.4 mmol) in ethanol (150 ml) was added a solution of potassium hydroxide (26.43 g ; 472 mmol) in water (100 ml) and the resulting mixture heated at reflux 5 overnight. The mixture was cooled and the ethanol removed by evaporation, the remaining aqueous phase was extracted with diethyl ether then acidified with 5N HCl. The acidic aqueous phase was then extracted with EtOAc (3 x 200 ml) and the combined organic layers washed with water, sat NaCl, dried over Na SO4, filtered and evaporated to give the title compound (19.91 g, 95%). 0
Description 96
2-Methoxy-4-(trifluoromethyl)benzaldehvde
Prepared using 2-methoxy-4-(trifluoromethyl)benzoic acid (Description 96) in place of 2-bromo-4-fluorobenzoic acid according to the procedures of Descriptions 77 and 78 respectively.
Description 97
2-hvdroχy-4-(trifluoromethyl)benzaldehvde
A mixture of 2-methoxy-4-trifluoromethyl benzaldehyde (Description 96; 18 g, 88 mmol) and hthium chloride (11.19 g ; 264 mmol) in anhydrous N,N- dimethylformamide (100 ml) was heated at reflux for 3 hours. The mixture was cooled and poured into water (200 ml), then acidified by the addition of IN HCl. The mixture was extracted with ether (3 x 200 ml) then the combined ether layers washed with water (2 x 600 ml), sat NaCl (100 ml), dried over Na2SO4, filtered and evaporated to give the title compound (16.25 g, 97%).
Description 98
6-(Trifluoromethyl)isoquinolin-5-amine
Prepared using 2-hydroxy-4-(trifluoromethyl)benzaldehyde (Description 97) in place of 2-hydroxy-δ-methoxy-3-nitrobenzaldehyde according to the procedures of Descriptions 81, 40, 41, 44, and 43 respectively.
Description 99
7-(Trifluoromethyl)isoquinohn-5-amine Prepared using 2-hydroxy-5-(trifluoromethyl)benzaldehyde [see WO-A-9962902] in place of 2-hydroxy-δ-methoxy-3-nitrobenzaldehyde according to the procedures of Descriptions 81, 40, 41, 44, and 43 respectively.
Description 100
5-Fluoro-l-methylindene
A solution of δ-fl.uoro-1-indanone (25 g, 0.17 mol) in dry THF (100 ml) was added dropwise to a solution of methyl magnesium bromide (70 ml of 3N in diethyl ether, 0.21 mol) in dry THF (50 ml) at 0°C. The mixture was stirred at RT
overnight. The reaction mixture was quenched with aq. HCl to pH 1 and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give the title compound as an oil (22.3 g, 91%).
Description 101
6-Fluoro-l-methvhsoquinoline
A solution of δ-fluoro-1-methylindene (Description 100, 22.3 g, O.lδ mol) in methanol (350 ml) was cooled to -78°C and ozonised for 9.5 h. The reaction mixture was purged with nitrogen and removed from the coohng bath. Sodium bicarbonate (20 g) and dimethyl sulfide (30 ml) were added and the reaction mixture stirred at RT for 6 hr. Ammonium hydroxide (200 ml) was then added and the reaction mixture stirred at RT for 48 hr. The resulting mixture was poured into water (1 htre) and extracted with dichloromethane (3 x 400 ml). The organic extracts were combined, washed with water and brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using an eluant system of 1% MeOH/ 99% DCM to give the title compound (1.4 g, 5.8%).
Description 102
6-Fluoro-l-methyl-5-nitroisoquinoline
Prepared by nitration of 6-fluoro-l-methyhsoquinoline (Description 101) according to the procedure of Description 44 to give the title compound (630 mg, 30%).
Description 103
6-Fluoro-l-methylisoquinolin-5-amine Prepared by reduction of 6-fluoro-l-methyl-δ-nitroisoquinoline (Description 102) according to the procedure of Description 43 to give the title compound (435 mg, 96%).
Description 104
5-Nitroisoquinohne- 1-carboxyhc acid
Isoquinohne-1-carboxyhc acid (3.98 g, 23.0 mmol) was dissolved in cone, sulfuric acid (16 ml) at 0 °C. A mixture of cone, sulfuric acid (5 ml) and fuming nitric acid (5 ml) was added over 10 min. and the reaction stirred for a further lh at 0 °C, then poured into ice-water (400 ml). The sohd was collected by filtration, then washed with water (100 ml), ethanol (100 ml) and ether (100 ml), then dried under vacuum to give the title compound (4.1 g, 82%).
10
Description 105
Methyl 5-nitroisoquinoline- 1-carboxylate
Potassium carbonate (23 g, 167 mmol) was added to a solution of δ-nitro- lδ isoquinohne- 1-carboxyhc acid (Description 104, 2.7 g, 12.4 mmol) in N,N- dimethylformamide (60 ml) at room temperature. Iodomethane (1.0 ml, 16.1 mmol) was then added and the reaction stirred at room temperature for 20 h.
Water (300ml) was added and the mixture was extracted with ethyl acetate (2 x
200 ml). The combined organic phases were washed with water (2 x 100 ml), 20 brine (100 ml) then dried (Na2SO4) and evaporated. Purification of the residue by column chromatography eluting with ethyl acetate - isohexane (7:13 increasing to
1:1) gave the title compound (δδ8 mg, 19%).
Description 106
2δ
Methyl 5-aminoisoquinohne- 1-carboxylate
Prepared by reduction of methyl δ-nitroisoquinohne-1-carboxylate (Description
105) according to the procedure of Description 45.
30 Description 107
Methyl-5-aminoisoquinohne-3-carboxylate
Prepared using isoquinoline-3-carboxylic acid in place of isoquinohne- 1-carboxyhc acid according to the procedures of Descriptions 104, 105 and 106 respectively. 35
Description 108
3-Chloro-5-nitroisoquinohne
3-Chloroisoquinohne (Description 49; 3.4 g, 20.7 mmol) was nitrated according to the method of Description 44. After addition of the base, the sohd was filtered off to give crude 3-chloro-5-nitroisoquinohne (9 g). A sample (6.8 g) was partitioned between ethyl acetate and 10% aqueous K-2CO3 solution (200 ml). The organic layer was extracted with more ethyl acetate (100 ml) and the combined organic phases dried (Na2SO ) and evaporated to give the title compound (2.10 g, 64%).
Description 109
3-(Oimethylamino)isoquinohn-5-amine
3-Chloro-5-nitroisoquinohne (Description 108, 160 mg, 0.767 mmol) was dissolved in 33% ethanohc dimethylamine (6 ml) and the mixture then heated in a sealed tube at 100 °C for 2.5 h. After coohng to room temperature the solvent and excess dimethylamine was evaporated and the residue reduced according to the procedure of Description 45 to give the title compound (85 mg, 59%).
Description 110
2-(4-Hydroxybut-l-ynyl)benzaldehvde
To a solution of 2-bromobenzaldehyde (10 g, 54 mmol) in anhydrous N,N- dimethylformamide (150 ml) was added 3-butyn-l-ol (6.13 ml, 81 mmol) and triethylamine (11.3 ml, 81 mmol), followed by copper (I) iodide (490 mg, 5.4 mmol) and Pd(PPh3)2Cl2 (1.9 g, 2.7mmol), and the mixture degassed three times and stirred at room temperature overnight. The mixture was poured into water (600 ml) and extracted with EtOAc (3 x 150 ml); the combined EtOAc layers were washed with water (2 x 250 ml), sat NaCl (100 ml), then dried over Na2SO4 , filtered and evaporated. The residue was purified by column chromatography on silica eluting with 50% Et2θ in isohexanes to give the title compound (8.5 g, 90%) as an orange oil.
Description 111
3-(2-Hvdroxyethyl)isoquinoline
A solution of 2-(4-hydroxybut-l-ynyl)benzaldehyde (Description 110; 8.50 g, 48.8 mmol) in 2M methanohc ammonia (122 ml, 244 mmol) contained in a Parr flask was heated at 80°C for 2 hours (approx 35 psi achieved). The cooled mixture was evaporated and the residue purified by column chromatography on sihca elution with a gradient rising from 1% MeOH in DCM + 0.5% NH4OH to 5% MeOH in DCM + 0.5% NH4OH to give the title compound (6.2 g, 73%) as a beige sohd.
Description 112
3-(2-Azidoethyl)isoquinohne
To a ice-bath cooled solution of 3-(2-hydroxyethyl)isoquinoline (Description 111; 4.85 g, 28 mmol) and triethylamine (5.07 ml, 36.4 mmol) in anhydrous dichloromethane (100 ml) was added slowly methanesulfonyl chloride (2.49 ml, 32.2 mmol), and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water (200 ml), sat NaCl (100 ml), dried over Na2SO4 , filtered and evaporated. The residue was dissolved in anhydrous N,N- dimethylformamide (100 ml) and sodium azide (2.00 g, 30.8 mmol) added and the resulting mixture stirred at room temperature for 4 days. The mixture was poured into water (400 ml), and extracted with EtOAc (3 x 100 ml). The combined EtOAc layers were washed with water (3 x 200 ml) , saturated aqueous NaCl (100 ml), dried over Na2SO4, filtered and evaporated to give the title compound (5.6 g, 100%).
Description 113
3-(2-Aminoethyl)isoquinoline To a solution of 3-(2-azidoethyl)isoquinohne (Description 112; 5.6 g, 28.3 mmol) in anhydrous tetrahydrofuran (50 ml) was added triphenylphosphine (14.85 g, 56.6 mmol) and water (0.509 ml, 28.3 mmol), and the resulting mixture stirred at room temperature overnight. The mixture was loaded directly onto a Bond-elut SCX cartridge and eluted with methanol until TLC indicated complete elution of
triphenylphosphine. The product was then eluted with 2.0M ammonia in methanol. The basic fractions were collected and evaporated to give the title compound (2.7 g, 55%).
Description 114
Ethyl 2-isoquinohn-3-ylethylcarbamate
To an ice-bath cooled solution of 3-(2-aminoethyl)isoquinohne (Description 113;
2.70 g, lδ.7 mmol) and triethylamine (2.84 ml, 20.41 mmol) in anhydrous dichloromethane (75 ml) was added slowly ethyl chloroformate (1.65 ml, 17.27 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water, sat NaCl, dried over Na2SO4 , filtered and evaporated. The residue was purified by column chromatography on sihca elution with a gradient rising from DCM to 2% MeOH in DCM + 0.5% NH4OH to give the title compound (2.27 g, 59%).
Description 115
Ethyl 2-(δ-aminoisoquinohn-3-yl)ethylcarbamate Prepared using ethyl 2-isoquinolin-3-ylethylcarbamate (Description 114) in place of 3-methyhsoquinohne according to the procedures of Descriptions 44 and 43 respectively.
Description 116
tert-Butyl 2-(5-aminoisoquinohn-3-yl)ethylcarbamate
To a solution of potassium hydroxide (450 mg ; 8.02 mmol) in ethanol was added ethyl 2-(5-aminoisoquinohn-3-yl)ethylcarbamate (Description llδ; 1.04 g, 2.6 mmol), and the resulting mixture heated at reflux until HPLC indicated the reaction was complete (approx 5 days). The mixture was cooled and loaded directly onto a Bond-elut SCX cartridge. The cartridge was washed with methanol, and the product then eluted with 2M ammonia in methanol. The basic fractions were evaporated and the residue dissolved in dichloromethane (lδ ml). Di-tert butyl dicarbonate (830 mg, 3.8 mmol) was added and the resulting
mixture stirred at room temperature for 1 hour, then evaporated to dryness to give the title compound (l.lg, 100%).
Description 117 δ
Isoquinohn-7-yl trifluoromethanesulfonate
7-Hydroxyisoquinohne (1.4 g, 9.6 mmol) and triethylamine (1.5 ml, 10.6 mmol) were added to ether (50 ml) under a nitrogen atmosphere at 0 °C. Trifluoromethylsulfonic anhydride (1.8 ml, 10.6 mmol) was added dropwise and 10 the mixture then warmed to room temperature for 3h. The layers were separated and the lower layer extracted with ether (2 x 100 ml). The combined organics were then dried (Na2SO4) and evaporated to give the title compound as a brown oh (1.04 g).
lδ Description 118
2-(Trifluoromethyl)pyrimidine-δ-carboxyhc acid
To a solution of methyl 2-trifluoromethyl pyrimidine-5-carboxylate [see
WO-A-0066667] (5 g, 22.7 mmol) in methanol (100 ml) was added a solution of
20 hthium hydroxide (1.09 g, 4δ.4 mmol) and the resulting mixture stirred at room temperature overnight. The methanol was removed by evaporation and the residue further diluted with water (50 ml). Extracted with EtOAc (x 3) and the aqueous phase was then acidified by the addition of c.HCl. The precipitate was extracted into EtOAc (x3) and the combined organic layers washed with sat NaCl,
25 dried over Na2SO4 , filtered and evaporated to give the title compound (2.0 g,
Description 119
30 δ-(Hydroxymethyl)-2-(trifluoromethv pyrimidine
To an ice-bath cooled solution of 2-(trifluoromethyl)pyrimichne-δ-carboxylic acid (Description 118; 2 g, 10.4 mmol) in anhydrous tetrahydrofuran (100 ml) was added dropwise borane tetrahydrofuran complex [l.OM solution in THF] (lδ.6 ml, 15.6 mmol), after complete addition the mixture was stirred at room temperature
for 90 mins. The reaction was quenched by the careful addition of water (2 ml), foUowed by saturated aqueous K2CO3. The organic layer was separated, and the aqueous phase extracted with Et2O. The combined organics were then washed with water, saturated NaCl, dried over Na2SO4 , filtered and evaporated to give the title compound (680 mg, 31%).
Description 120
5-Azidomethyl-2-(trifluoromethyl)pyrimidine To a solution of δ-(hydroxymethyl)-2-(trifluoromethyl)pyrimidine (Description 119; 680 mg, 3.26 mmol) and triethylamine (0.65 ml, 3.91 mmol) in anhydrous dichloromethane (15 ml) cooled in an ice-bath was added dropwise methanesulfonyl chloride (0.28 ml, 3.59 mmol), and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water and sat NaCl , dried over Na2SO4 , filtered and evaporated. The residue was dissolved in anhydrous N,N-dimethylformamide (15 ml), sodium azide (233 mg, 3.59 mmol) was added and the resulting mixture stirred at room temperature overnight. The mixture was poured into water (100 ml) and extracted with EtOAc (3 x 15 ml). The combined EtOAc layers were washed with water (2 x 50 ml), saturated NaCl (25 ml), dried over Na2SO4 , filtered and evaporated to give the title compound (660 mg, 100%).
Description 121
5-(Aminomethyl)-2-(trifluoromethyl')pyrimidine
To a solution of 5-(azidomethyl)-2-(trifluoromethyl)pyrimidine (Description 120; 660mg, 3.26mmol) in anhydrous THF (10 ml) was added triphenylphosphine (1.71g, 6.52mmol) and water (0.059ml, 3.26mmol) and the resulting mixture stirred at room temperature overnight. The mixture was evaporated and the residue purified by column chromatography on sihca elution with 5% MeOH in DCM + 0.5% NH4OH to give the title compound (320 mg, 5δ%) as a pale yellow sohd.
Description 122
4-(Morphohn-4-ylmethyl)benzonitrile
To a solution of 4-cyanobenzylbromide (1.0 g, 5.1 mmol) in MeCN (10 ml) was 5 added morpholine (0.44 g, 0.44 ml, 5.1 mmol) and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and partioned between CH2CI2 and NaOH (2M). The organic layer was separated, dried over MgSO4 and dried to give the desired nitrile (0.70 g, 68 %).
10 Description 123
4-uVIorphohn-4-ylmethyl)benzylamine
To a suspension of 4-(morphohn-4-ylmethyl)benzonitrile (Description 122, 0.5 g,
2.5 mmol) in THF (7 mL) at 0°C was added dropwise a solution of LiAhBU (1.0 M lδ in THF, 2.δ ml, 2.5 mmol). The reaction was stirred at 0°C for lh. Additional LiAlH4 (1.0 M in THF, 1.0 ml, 1.0 mmol) was added and the reaction stirred for an additional 30 min. The reaction was quenched by the addition of water (0.13 mL) followed by 15 % NaOH solution (0.13 ml) and stirred vigorously for 1 h. The reaction was filtered through cehte, evaporated and azeotroped twice with
20 toluene. The amine was used crude.
Description 124
2-(2-Morphohn-4-ylethoxy)-4-(trifluoromethyl)benzonitrile 25 To a solution of 2-nitro-4-trifluoromethyl benzonitrile (0.5 g, 2.3 mmol) and 2- morphohn-4-yl-ethanol (0.37 g, 0.34 ml, 2.8 mmol) in DMF (4 ml) was added dropwise a solution of KOH (0.23 g, 4.1 mmol) in water (1.5 ml). After 10 min the reaction was poured into ice water and the white crystalline product collected by filtration, washed with water and dried (0.5 g, 72 %). 30
Description 125
2-(2-Morphohn-4-ylethoxy)-4-(trifluoromethyl)benzylamine To a solution of 2-(2-morphohn-4-ylethoxy)-4-(trifluoromethyl)benzonitrile (Description 124, 0.5 g, 1.67 mmol) in ethanol (30 ml) was added aqueous ammonia (33 % aq soln, 5 ml) and a slurry of 10 % Pd/C catalyst in water. The reaction was hydrogenated at 43 psi. After 45 min the reaction was complete. The catalyst was filtered off, the reaction condensed and the product azeotroped with toluene to give the desired amine (0.49 g, 96 %).
Description 126
Isoquinohne-5-carbonyl azide
Isoquinohne-5-carboxyhc acid monohydrate (5.00 g, 26.2 mmol) was suspended in dichloromethane (200 ml) and N,N-dimethylformamide (5 drops) added. Oxalyl chloride (4.57 ml, 52 mmol) was then added and the reaction stirred for 7h. The solvent and excess oxalyl chloride was then evaporated and the residue taken up in dichloromethane (200 ml). A solution of sodium azide (2.1 g, 32.3 mmol) and tetra-n-butylammonium bromide (850 mg) in water (50 ml) was then added in one portion and the mixture stirred for 20 min. The layers were separated and the aqueous phase extracted with more dichloromethane (100 ml). The combined organic phases were evaporated and the residue purified by flash column chromatography (eluant ethyl acetate - dichloromethane (1:4)) to give the title compound as a yellow sohd (2.27 g, 44 %).
Example 1
N-Benzyl-iV-isoquinohn-5-ylurea
Prepared from 5-aminoisoquinohne and benzyl isocyanate according to the procedure of Description 61. m/z (ES+) 278 (M + H)+.
Examples 2 to 16 were prepared according to the procedure of Description 60.
Example 2
Ar-(l.l'-Biphenyl-4-ylmethyl)-N1-isoquinohn-5-ylurea
Prepared from isoquinoline-5-carboxyhc acid [see WO 95/09843] and
4-phenylbenzylamine. m/z (ES+) 354 (M + H)+.
Example 3
N-(l.l'-Biphenyl-3-ylmethyl)-A^-isoquinohn-5-ylurea
Prepared from isoquinohne-5-carboxyhc acid and 3-phenylbenzylamine. m/z (ES+) 354 (M + H)+.
Example 4
N-Isoquinohn-5-yl-iV-(3-phenylpropyl)urea
Prepared from isoquinoline-5-carboxylic acid and 3-phenylpropylamine. m/z (ES+) 306 (M + H)+.
Example 5
N-Isoq uinohn- 5 -yl-iV -(1.2.3.4-tetrahvdronaphthalen-2- ylmethvDurea
Prepared from isoquinohne-δ-carboxyhc acid and l,2,3,4-tetrahydronaphthalen-2- ylmethylamine (Description 20). m/z (ES+) 332 (M + H)+.
Example 6
N-[2-(4-Chlorophenyl)ethyll-iV-isoquinolin-5-ylurea
Prepared from isoquinohne-5-carboxyhc acid and 2-(4-chlorophenyl)ethylamine. m/z (ES+) 326 (M + H)+.
Example 7
N-[3.δ-bis(Trifluoromethyl)benzyll-N-isoquinohn-5-ylurea Prepared from isoquinohne-δ-carboxyhc acid and 3,5-bis(trifluoromethyl)benzylamine. m/z (ES+) 414 (M + H)+.
Example 8
N-[3-(3.4-dimethylphenyl)propyll-N-isoquinohn-5-ylurea
Prepared from isoquinohne-δ-carboxyhc acid and 3-(3,4-dimethylphenyl)- propylamine. m/z (ES+) 334 (M + H)+.
Example 9
N-(4-ferf-Butylbenzyl)-.-V-isoquinohn-8-ylurea
Prepared from isoquinohne-8-carboxyhc acid and 4-terf-butylbenzylamine. m/z (ES+) 334 (M + H)+.
10
Example 10
N-(4-ter -Butylbenzyl)-N-isoquinolin-δ-ylurea
Prepared from isoquinoline-5-carboxyhc acid and 4-tert-butylbenzylamine. m/z (ES+) 334 (M + H)+. lδ
Example 11
N-(4-fert-Butylbenzyl)-N-quinolin-δ-ylurea
Prepared from quinoline-5-carboxyhc acid [see WO 96/09843] and 4-tert- butylbenzylamine. m/z (ES+) 334 (M + H)+.
20
Example 12
N-(3-ter^-Butylbenzyl -iV-isoquinohn-5-ylurea
Prepared from isoquinohne-δ-carboxyhc acid and 3-tert-butylbenzylamine
(Description 9). m/z (ES+) 334 (M + H)+.
2δ
Example 13
N-[2-(4-tert-Butylphenyl)ethyl1-N-isoquinohn-δ-ylurea Prepared from isoquinoline-5-carboxylic acid and 2-(4-teτX butylphenyl)ethylamine. m/z (ES+) 348 (M + H)+.
30
Example 14
N-Isoquinohn-5-yl-N-[4-(trifluoromethyl)benzyllurea
Prepared from isoquinoline-5-carboxylic acid and 4-trifluoromethylbenzylamine. m/z (ES+) 346 (M + H)+.
Example 15
N-Isoquinohn-5-yl-iV-[3-(trifluoromethyl)benzyl1urea
Prepared from isoquinohne-5-carboxyhc acid and 3-trifluoromethylbenzylamine. m/z (ES+) 346 (M + H)+.
10
Example 16
N-Isoquinohn-5-yl-N'-{2-[4-(trifluoromethyl phenyllethyl}urea Prepared from isoquinohne-δ-carboxyhc acid and 2-[4-(trifluoromethyl)phenyl]ethylamine (Description 6). m/z (ES+) 360 (M + H)+. lδ
Example 17
N-(2-Oxidoisoquinohn-δ-yl)-N-l4-(trifluoromethyl)benzyl]urea
To a suspension of N-isoquinohn-5-yl-N'-[4-(trifluoromethyl)benzyl]urea
(Example 14; 100 mg , 0.29 mmol) in chloroform (25 ml) was added Oxone
20 (541 mg, 0.87 mmol), foUowed by wet alumina Grade III (lg), and the resulting suspension heated at reflux for 60 minutes. Whilst the mixture was still hot it was filtered to remove alumina and Oxone, the sohds were washed with more chloroform, then methanol, and the filtrate evaporated to dryness. The residue was purified by preparative TLC eluting with 10% MeOH in dichloromethane +
25 0.5% NH4OH, and the product triturated with a mixture of dichloromethane/iso- hexanes, filtered and dried to give the title compound (11 mg, 10%) as a white sohd. m/z (ES+) 362 (M + H)+.
Examples 18 to 51 were prepared according to the procedure of Description 60.
30
Example 18
N-Isoquinohn-5-yl-iV1-{2-[3-(trifluoromethyl)phenyllethyl>urea Prepared from isoquinohne-δ-carboxyhc acid and 2-[3-(trifluoromethyl)phenyl]ethylamine. m/z (ES+) 360 (M + H)+.
Example 19
N-Isoquinohn-δ-yl-N-{3-[4-(trifluoromethv phenynpropyllurea Prepared from isoquinohne-5-carboxyhc acid and δ 3-[4-(trifluoromethyl)phenyl]propylamine (Description 22). m/z (ES+) 374 (M + H)+.
Example 20
N-Isoquinohn-δ-yl-N-^-ftrifluoromethyDbenzyllurea 0 Prepared from isoquinoline-8-carboxylic acid and 4-(trifluoromethyl)benzylamine.
Example 21
N-[3-Fluoro-4-(trifluoromethyl)benzyl]-N-isoquinohn-δ-ylurea 5 Prepared from isoquinohne-δ-carboxyhc acid and 3-fluoro-4- (trifluoromethyl)benzylamine. m/z (ES+) 364 (M + H)+.
Example 22
N- r2-Fluoro-4-(trifl.uoromethyl)benzyl] - JV-isoquinohn-δ-ylurea 0 Prepared from isoquinoline-δ-carboxyhc acid and 2-fluoro-4- (trifluoromethyl)benzylamine. m/z (ES+) 364 (M + H)+.
Example 23
N-Isoqxιinohn-δ-yl-N-{3-r3-(trifluoromethyl)phenvnpropyl>urea δ Prepared from isoquinoline-5-carboxyhc acid and
3-[3-(trifluoromethyl)phenyl]propylamine (Description 23). m/z (ES+) 374 (M + H)+.
Example 24 0 N-Isoquinohn-δ-yl-iV-r4-(trifluoromethoxy)benzyllurea Prepared from isoquinoline-5-carboxyhc acid and 4-(trifluoromethoxy)benzylamine. m/z (ES+) 362 (M + H)+.
Example 25
Ar-{[6-(4-Fluorophenyl)pyridin-3-yl]methv -iV1-isoquinohn-5-ylurea Prepared from isoquinohne-δ-carboxyhc acid and [6-(4-fluorophenyl)pyridin-3- yl]methylamine (Description 26). m/z (ES+) 373 (M + H)+.
Example 26 ■Λr-Isoquinohn-8-yl-iV-{3-r4-(trifluoromethyl)phenyllpropyl)urea Prepared from isoquinohne-8-carboxyhc acid and 3-[4-(trifluoromethyl)phenyl]propylamine (Description 22). m/z (ES+) 374 (M + H)+.
Example 27
N-Quinolin-δ-yl-N-{3-[4-(trifluoromethyl)phenyl]propyl)urea Prepared from quinohne-5-carboxyhc acid and 3-[4-(trifluoromethyl)phenyl]propylamine (Description 22). m/z (ES+) 374 (M + H)+.
Example 28
N-Isoquinohn-8-yl-N-(3-r3-(trifluoromethyl)phenvnpropyl)urea Prepared from isoquinohne-8-carboxyhc acid and
3-[3-(trifluoromethyl)phenyl]propylamine (Description 23). m/z (ES+) 374 (M + H)+.
Example 29 N-Quinohn-5-yl-iV-l3-[3-(trifluoromethyl)phenyl1propyl)urea Prepared from quinohne-δ-carboxyhc acid and 3-[3-(trifluoromethyl)phenyl]propylamine (Description 23). m/z (ES+) 374 (M + H)+.
Example 30
N-Isoquinohn-8-yl-N-r4-(trifluoromethoxy)benzyllurea Prepared from isoquinohne-8-carboxyhc acid and 4-(trifluoromethoxy)benzylamine. m/z (ES+) 362 (M + H)+.
Example 31
N-Qιnnohn-δ-yl-Λ 4-(trifluoromethoxy)benzyIlurea
Prepared from quinohne-5-carboxyhc acid and 4-(trifluoromethoxy)benzylamine. δ m/z (ES+) 362 (M + H)+.
Example 32
N-(2.3-Dihvdro- lH-inden-2-ylmethyl)-iV-isoquinohn-5-ylurea Prepared from isoquinoline-δ-carboxyhc acid and 2,3-dihydro-lH-inden-2- 10 ylmethylamine. m/z (ES+) 318 (M + Η)+.
Example 33
N-Isoquinohn-δ-yl-N-(4-phenylcvclohexyl)urea
Prepared from isoquinohne-δ-carboxyhc acid and 4-phenylcyclohexylamine. lδ m/z (ES+) 346 (M + H)+.
Example 34
N-Isoquinohn-δ-yl-N-(6.7.8.9-tetrahvdro-5H-benzo[ ]r71annulen-6-ylmethyl)urea Prepared from isoquinohne-δ-carboxyhc acid and 6,7,8,9-tetrahydro-δH- 20 benzo[α][7]annulen-6-ylmethylamine hydrochloride (Description 26). m/s (ES+) 346 (M + Η)+.
Example 35
N-Isoquinohn-5-yl-JV,-(6.7.8.9-tetrahydro-δH-benzo[αir71annulen-7-ylmethyl)urea 25 Prepared from isoquinohne-5-carboxyhc acid and 6,7,8,9-tetrahydro-δH- benzo[ ] [7] annulen- 7-ylmethylamine hydrochloride (Description 28). m/z (ES+) 346 (M + Η)+.
Example 36
30 N-isoquinolin-δ-yl-N-{[5-(trifluoromethvDpyridin-2-yllmethyllurea Prepared from isoquinohne-δ-carboxyhc acid and 2-aminomethyl-5- (trifluoromethyl)pyridine (Description 2). m/z (ES+) 347 (M + H)+.
Example 37
N-[(4-ter^-Butylpyridin-2-yl)methyll-iv1-isoquinohn-5-ylurea
Prepared from isoquinohne-5-carboxyhc acid and 2-aminomethyl-4-ter£- butylpyridine (Description 5). m/z (ES+) 335 (M + H)+.
Example 38
N- [(6-ter^Butylpyri( n-3-yl)methvIl -JV-isoquinolin-5-ylurea
Prepared from isoquinohne-5-carboxyhc acid and 3-aminomethyl-6-terf- butylpyridine (Description 11). m/z (ES+) 335 (M + H)+.
Example 39
JV- [(2-ter^-Butylpyridin-4-yl')methyl] -JV-isoquinolin-5-ylurea
Prepared from isoquinohne-5-carboxyhc acid and 4-aminomethyl-2-tert- butylpyridine (Description 13). m/z (ES+) 335 (M + H)+.
Example 40
JV- [(6-fert-Butylpyridin-2-yl)methyn -N-isoquinolin-5-ylurea
Prepared from isoquinoline-5-carboxyhc acid and 2-aminomethyl-6-ter£- butylpyridine (Description 16). m/z (ES+) 335 (M + H)+.
Example 41
N-Isoquinohn-5-yl-JV-{[6-(trifluoromethyl)pyridin-3-yllmethyllurea Prepared from isoquinoline-5-carboxyhc acid and 3-aminomethyl-6- (trifluoromethyl)pyridine. m/z (ES+) 347 (M + H)+.
Example 42
N-Isoquinohn-5-yl-JV-{3-r6-(trifluoromethyl)pyridin-3-yllpropyl urea
Prepared from isoquinohne-5-carboxyhc acid and 3-[6-(trifluoromethyl)pyridin-3- yl]propylamine (Description 18). m/z (ES+) 375 (M + H)+.
Example 43
JV-Isoquinohn-5-yl-JV-[3-(lH-pyrazol-l-yl benzyllurea
Prepared from isoquinohne-5-carboxyhc acid and 3-(lH-pyrazol-l-yl)benzylamine hydrochloride (Description 29). m/z (ES+) 344 (M + Η)+.
Example 44
JV-Isoquinohn-5-yl-JV-[4-(lH-pyrazol-l-yl)benzvnurea
Prepared from isoqιιinoline-5-carboxylic acid and 4-(lH-pyrazol-l-yl)benzylamine hydrochloride (Description 30). m/z (ES+) 344 (M + Η)+.
Example 45
JV-Isoquinohn-5-yl-JV-r(2-phenyl-1.3-thiazol-5-yl)methyllurea
Prepared from isoquinohne-5-carboxyhc acid and (2-phenyl-l,3-thiazol-δ- yl)methylamine. m/z (ES+) 361 (M + H)+.
Example 46
N-Isoquinolin-5-yl-JV-[(2-thien-2-yl-1.3-thiazol-4-yl)methyllurea
Prepared from isoquinohne-δ-carboxyhc acid and (2-thien-2-yl-l,3-thiazol-4- yl)methylamine. m/z (ES+) 367 (M + H)+.
Example 47
JV-Isoquinohn-δ-yl-JV- [(4-phenyl- 1.3-thiazol-2-yl)methyl] urea
Prepared from isoquinoline-δ-carboxylic acid and (4-phenyl-l,3-thiazol-2- yl)methylamine. m/z (ES+) 361 (M + H)+.
Example 48
N-Isoquinohn-δ-yl-JV- [(2-phenyl- 1.3-thiazol-4-yl)methyl] urea
Prepared from isoquinohne-δ-carboxyhc acid and (2-phenyl-l,3-thiazol-4- yl)methylamine. m/z (ES+) 361 (M + H)+.
Example 49
N-Isoquinohn-5-yl-JV-[2-(4-phenyl-1.3-thiazol-2-yl)ethyllurea
Prepared from isoquinoline-5-carboxylic acid and 2-(4-phenyl-l,3-thiazol-2- yl)ethylamine. /z (ES+) 375 (M + H)+.
Example 50
N-Isoquinohn-5-yl-JV-[(5-phenvhsoxazol-3-yl)methvnurea
Prepared from isoquinohne-5-carboxyhc acid and (5-phenylisoxazol-3- yl)methylamine. m/z (ES+) 345 (M + H)+.
Example 51
N-Isoquinohn-5-yl-JV-[(3-phenvhsoxazol-5-yl)methyl1urea
Prepared from isoquinoline-5-earboxylic acid and (3-phenyhsoxazol-5- yl)methylamine. m/z (ES+) 346 (M + H)+.
Example 52
N-(8-Fluoroisoquinohn-δ-yl)-JV-r4-(trifluoromethyl)benzyl]urea Prepared from 8-fluoroisoquinohn-5-amine (Description 43) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 364 (M + H)+.
Example 53
N-Isoquinohn-δ-yl-N-methyl-JV-^-faifluoromethvDbenzyllurea Sodium hydride (60 % dispersion in oil, 7 mg, 0.17 mmol) was added to a suspension N-isoquinolin-δ-yl-JV-[4-(trifluoromethyl)benzyl]urea (Example 14; 48 mg, 0.14 mmol) in THF (3 mL) at room temperature and the reaction was stirred until effervescence ceased (20 minutes). Methyl iodide (11 μL, 0.17 mmol) was added and the reaction stirred at room temperature for 3 hours. TLC analysis (10 % MeOH in CH2CI2) indicated only one major product. The reaction was evaporated in vacuo and the product isolated by preparative TLC (4 % MeOH in CH2CI2) to give the title compound, m/z (ES+) 360 (M + H)+.
Examples 54 to 60 were prepared according to the procedure of Description 60.
Example 54
JV-Isoquinolin-δ-yl-N-methyl-N-[4-(trifluoromethyl)benzyl]urea Prepared from isoquinohne-5-carboxyhc acid and N-methyl-N-[4- (trifluoromethyl)benzyl] amine (Description 31). m/z (ES+) 190 (M + H)+.
Example 55 JV-Isoquinohn-5-yl-JV-{l-[4-(trifluoromethyl)phenyllethyl)urea Prepared from isoquinohne-δ-carboxyhc acid and l-[4-(trifluoromethyl)phenyl]ethylamine (Description 32). m/z (ES+) 360 (M + H)+.
Example 56
N-(1.3-Diphenylpropyl)-JV-isoquinohn-5-ylurea
Prepared from isoquinoline-5-carboxylie acid and 1,3-diphenylpropylamine (Description 33). m/z (ES+) 382 (M + H)+.
Example 57
N-Isoquinohn-5-yl-JV-[(3-phenyl-1.2.4-oxadiazol-5-yl)methvnurea Prepared from isoquinohne-5-carboxyhc acid and (3-phenyl-l,2,4-oxadiazol-5- yl)methylamine hydrochloride (Description 34). m/z (ES+) 346 (M + H)+.
Example 58
N- [(2-Benzyl- 1.3-thiazol-4-yl)methyll -JV-isoquinohn-5-ylurea Prepared from isoquinoline-5-carboxylic acid and 2-benzyl-l,3-thiazol-4- yl)methylamine (Description 35). m/z (ES+) 375 (M + H)+.
Example 59
N-Isoquinolin-5-yl-JV-{[l-(2-methylphenyl)-lH-Pyrazol-4-yl]methvhurea Prepared from isoquinoline-5-carboxyhc acid and [l-(2-methylphenyl)-lH- pyrazol-4-yl]methylamine (Description 36). m/z (ES+) 358 (M + Η)+.
Example 60
JV-(3-Methoxyisoquinohn-8-yl)-JV- 4-(trifluoromethyl)benzvnurea Prepared from 3-methoxyisoquinoline-8-carboxylic acid (Description 56) and 4- (trifluoromethyl)benzylamine. m/z (ES+) 376 (M + H)+.
Example 61 JV-Cinnohn-5-yl-JV-r4-(trifluoromethyl)benzyllurea Prepared from cinnohn-5-amine (Sci Pharm. 1982, 50, 246) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 347 (M + H)+.
Examples 62 to 64 were prepared according to the procedure of Description 60.
Example 62 N-(4-fer^Butylbenzyl)-N'-cinnohn-δ-ylurea
Prepared from cinnohn-5-amine (Sci Pharm. 1982, 50, 246) and (A-tert- butylbenzyl) acetic acid, m/z (ES+) 335 (M + H)+.
Example 63 N-(3-Cyclohexylpropyl)-JV-isoquinohn-5-ylurea
Prepared from isoquinohne-δ-carboxyhc acid and 3-cyclohexylpropylamine hydrochloride (Description 37). m/z (ES+) 312 (M + H)+.
Example 64 JV-Isoquinohn-5-yl-JV-(6.7.8.9-tetrahydro-δH-benzo[αl T71 annulen- 7-yl)urea Prepared from isoquinohn-5-amine and 6,7,8,9-tetrahydro-δH- benzo[α][7]annulene-7-carboxylie acid (Description 38). m/z (ES+) 332 (M + Η)+.
Example 65 N-Isoquinohn-5-yl-JV-r4-(trifluoromethyl)benzyllthiourea
To a solution of l,l'-thiocarbonyldi-2(lH)-pyridone (330 mg, 1.4 mmol) in dichloromethane (13 ml) under nitrogen was added, dropwise, a solution of 4-(trifluoromethyl)benzylamine (200 μl, 1.4 mmol) in dichloromethane (10 ml).
The solution was stirred at room temperature for 16 hours. 5-Aminoisoquinohne (245 mg, 0.0017 mol) was added to the reaction mixture, which was then heated at reflux for 2 days and evaporated. Preparative TLC (eluant 5% methanol/ 95% dichloromethane) gave a product band also containing 5-aminoisoquinoline. The mixed product (230 mg) was dissolved in acetonitrile (40 ml) and tetrafluorophthahc anhydride (700 mg, 3.2 mmol) was added. The reaction was stirred at room temperature for 16 hours. Ethyl acetate (60 ml) was added to the reaction mix which was then washed with saturated aqueous sodium bicarbonate (3 x 20 ml). The organic extract was evaporated and the residue purified by preparative TLC (eluant system 5% methanol/ 95% dichloromethane) to give the title compound (77 mg, 23%). m/z (ES+) 362 (M + 1)+.
Example 66
N-Isoquinohn-6-yl- JV- [4-(trifluoromethyl)benzyl] urea Prepared from 6-aminoisoquinohne (Description 51) and
[4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 346 (M + H)+.
Example 67 N-Isoquinohn-6-yl-JV-r4-(trifluoromethoxy)benzyl]urea Prepared from 6-aminoisoquinohne (Description 51) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 362 (M + H)+.
Example 68
N-(3-Methyhsoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea Prepared from 3-methyhsoquinohn-5-amine (Description 45) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 360 (M + H)+.
Example 69
JV-(l-Chloroisoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzvnurea Prepared from l-chloroisoquinohn-5-amine (Description 48) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 380, 382 (M + H)+.
Example 70
N-[l-(Dimethylamino)isoquinohn-5-yll-JV-[4-(trifluoromethyl)benzyl]urea N-(l-Chloroisoquinohn-5-yl)-N-(4-trifluoromethylbenzyl)urea (Example 69; 60 mg) was suspended in ethanol (5 ml). Ethanohc dimethylamine (33%, 2 ml) was added and the mixture heated to 100 °C in a sealed tube for 16 hours after which time TLC indicated complete reaction. The reaction mixture was evaporated and the residue purified by preparative thin layer chromatography (5% methanol-dichloromethane eluant) to give the title compound (20 mg). m/z (ES+) 389 (M + H)+.
Example 71
JV-(3-Methvhsoquinohn-δ-yl)-JV-[4-(trifluoromethoxy)benzyl]urea Prepared from 3-methyhsoquinolin-5-amine (Description 46) and [4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 376 (M + H)+.
Example 72
^-(S-Methyhsoquinohn-δ-vD-N'-^-faifluoromethvDbenzyllurea A sample of 3-methyl-5-nitroisoquinohne (Description 44) enriched in the nitration byproduct 3-methyl-8-nitroisoquinohne was reduced according to
Description 4δ and the mixture of amines reacted with
[4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. Isomer separation of the products gave the title compound. m/z (ES÷) 360 (M + H)+.
Example 73
JV-(3-Chloroisoquinohn-δ-yl)-JV-[4-(trifluoromethyl)benzvnurea Prepared from 3-chloroisoquinohn-5-amine (Description 60) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 380, 382 (M + H)+.
Example 74 JV-(3-Methylcinnohn-δ-yl -JV-[4-(trifluoromethyl)benzyl1urea Prepared from 3-methylcinnolin-5-amine and [4-(trifluoromethyl)benzyl]isocyanate (Description 68) according to the procedure of Description 61. m/z (ES+) 361 (M + H)+.
Example 75
JV-Cinnohn-5-yl-JV-[4-(trifluoromethoxy)benzyl1urea Prepared from cinnohn-5-amine [Sci Pharm. 1982, 50, 246] and
[4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 363 (M + H)+.
Example 76 N-(l-hvdroxyisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzvnurea
N-(l-chloroisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea (Example 69; 47 mg, 0.12 mmol) was added to a mixture of 3N HCl (aq. 5 ml) and THF (1 ml). The mixture was heated at 90 °C for 20 hours, then 6N HCl (aq. 2 ml) was added and the reaction heated at 90 °C for a further 20 hours. After coohng to room temperature, ethyl acetate (20 ml) was added and the layers separated (some sohd was suspended in the organic layer). The organic phase was washed with saturated aqueous NaHCOβ (20 ml), then evaporated. The residue was triturated in refluxing isopropyl alcohol (5 ml), then cooled to room temperature. The white sohd was collected by filtration and washed with isopropyl alcohol (2 1 ml) to give the title compound (22 mg). m/z (ES+) 362 (M + H)+.
Example 77
N-f4-(trifluoromethyl)benzyl1-JV-[3-(trifluoromethyl)isoquinohn-5-yllurea Prepared from 3-(trifluoromethyl)isoquinohn-5-amine (Description 64) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 414 (M + H)+.
Example 78
N-(l-chloro-3-ethyhsoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzyllurea Prepared from l-chloro-3-ethyhsoqxιinolin-5-amine (Description 66) and [4- (trifluoromethyl)benzyl] isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 408 , 410 (M + H)+.
The following quinohn-6-yl derivatives were also prepared by similar methodology:
Example 79 N-phenyl-N'- [quinohn-6-vH urea Prepared from 6-aminoquinohne and phenyl isocyanate. m/z (ES+) 264 (M + H)+.
Example 80
N-(2-naphthyl)-N'-[quinohn-6-yllurea
Prepared from 6-aminoquinohne and 2-naphthyl isocyanate. m/z (ES+) 314 (M + H)+.
Example 81
N-(4-nitrophenyl)-Nf-[quinohn-6-yl1urea
Prepared from 6-aminoquinoline and 4-nitrophenyl isocyanate. /z (ES+) 309 (M + H)+.
Example 82
N- f3.5-bis(trifluoromethyl)phenyll -JV- rquinohn-6-yll urea
Prepared from 6-aminoquinohne and 3,5-bis(trifluoromethyl)phenyl isocyanate.
Example 83
JV-(4-phenoxyphenyl)-N'-[quinohn-6-yl1urea
Prepared from 6-aminoquinohne and 4-phenoxyphenyl isocyanate. 5 7tt/£ (ES+) 356 (M + H)+.
Example 84
N-(4-acetylphenyl)-N-fquinohn-6-yl]urea
Prepared from 6-aminoquinohne and 4-acetylphenyl isocyanate. 10 m/z (ES+) 306 (M + H)+.
Example 85
N-benzyl-Nf-[quinohn-6-yllurea
Prepared from 6-aminoquinohne and benzyl isocyanate. m/z (ES+) 278 (M + H)+. lδ
Example 86
N-[quinohn-6-yll-N'-[4-(trifluoromethoxy)phenyllurea
Prepared from 6-aminoquinohne and 4-(trifluoromethoxy)phenyl isocyanate. m/z (ES+) 348 (M + H)+.
20
Example 87
N-(4-cyanophenyl)-N'-[quinohn-6-yl]urea
Prepared from 6-aminoquinohne and 4-cyanophenyl isocyanate. m/z (ES+) 289 (M + H)+.
26
Example 88
JV-(l.l'-biphenyl-4-yl)-N,-lquinohn-6-yllurea
Prepared from 6-aminoquinohne and 4-biphenyl isocyanate. m/z (ES+) 340 (M + H)+.
30
Example 89
N- f4- (dimethylamino)phenyl] -JV - [qυinohn- 6- yll urea
Prepared from 6-aminoquinohne and 4-(dimethylamino)phenyl isocyanate.
m/s (ES+) 307 (M + H)+.
Example 90
N-(1.3-benzodioxol-δ-yl)-N'-[quinohn-6-yl]urea Prepared from 6-aminoquinohne and 3,4-(methylenedioxy)phenyl isocyanate. m/z (ES+) 308 (M + H)+.
Example 91
N-cyclohexyl-N'- [qxιinolin-6-yll urea Prepared from 6-aminoquinohne and cyclohexyl isocyanate. m/z (ES+) 270 (M + H)+.
Example 92
JV- [(+/- - 1-phenylethyl] -JV'- [quinohn-6-yl] urea Prepared from 6-aminoquinohne and (+/-)- 1-phenylethyl isocyanate. m/z (ES+) 292 (M + H)+.
The above exemplified compounds of the present invention have been tested in the following assay and generally possess an IC50 < 1 μM and, in the majority of cases, < 200 nM.
Biological Methodology
Determination of in vitro activity
CHO cells, stably expressing recombinant human VRl receptors and plated into black-sided 384-well plates, were washed twice with assay buffer (Hepes-buffered sahne) and then incubated with luM Fluo-3-AM for 60 minutes in darkness. Cells were washed twice more to remove excess dye, before being placed, along with plates containing capsaicin and test compounds in a Molecular Devices FLIPR. The FLIPR simultaneously performed automated pharmacological additions and recorded fluorescence emmission from Fluo-3. In all experiments, basal fluorescence was recorded, before addition of test compounds and subsequent addition of a previously determined concentration of capsaicin that evoked 80% of the maximum respsonse. Inhibition of capsaicin evoked increases in intracellular [Ca2+] were expressed relative to wells on the same plate to which
capcaicin was added in the absence of test compounds. Increases in intracellular [Ca2+] occuring after addition of test compound alone, prior to addition of capsaicin, allow determination of intrinsic agonist or partial agonist activity, if present. 5
Determination of in vivo efficacy in a capsaicin paw flinch model (Method adapted from Taniguchi et al, 1997, Br J Pharmacol. 122(5):809-12) To determine in vivo functional occupancy of VRl receptors, compounds are administered orally to male Sprague Dawley rats typically 1 hour prior to
10 receiving an intraplantar injection of capsaicin (2μg dissolved in ethanol) and the number of flinches of the injected paw is recorded for δ minutes immediately thereafter. Statistical analysis is performed using one-way ANOVA followed by Dunnett's test; p values <0.0δ compared to capsaicin/vehicle-treated rats are considered significant. lδ
Determination of in vivo efficacy in a model of inflammatory pain (Method adapted from Hargreaves et al, 1988 Pain, 32(l):77-88). Antinociceptive activity is determined using a rat carrageenan-induced thermal hyperalgesia assay. Inflammatory hyperalgesia is induced by intraplantar
20 injection of carrageenan (lambda-carrageenan 0.1 ml of 1% solution made up in sahne) into one hind paw. Compounds are given oraUy typically 2 hours after carrageenan and paw withdrawal latancies determined 1 hour later. Paw withdrawal latencies to apphcation of noxious thermal stimuh to plantar surface of the hind paw are measured using the Hargreaves apparatus. Thermal
26 hyperalgesia is defined as the difference in paw withdrawal latencies for sahne/vehicle- and carrageenan/vehicle-treated rats. Paw wthdrawal latencies for drug treated rats are expressed as a percentage of this response. Statistical analysis is performed using one-way ANOVA foUowed by Dunnett's test; p values <0.05 compared to carrageenan/vehicle-treated rats are considered significant.
30
Example 93
JV-(l-Methylisoquinohn-δ-yl)-JV-[4-(trifluoromethyl)benzyl1urea Prepared from l-methyhsoquinohn-5-amine (Description 68) and [4-(trifluoromethyl)benzyl]isocyanate (Description 68) according to the procedure of Description 61. m/z (ES+) 360 (M + H)+.
Example 94
N-(l-Methyhsoquinohn-δ-yl)-JV-[4-(trifluoromethoxy)benzyllurea Prepared from 1-methyhsoquinolin-δ-amine (Description 68) and [4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 376 (M + H)+.
Example 95
N-(6.8-Difluoro-3-methvhsoquinohn-5-yl)-N'-r4-(trifluoromethyl)benzyllurea Prepared from 6,8-difluoro-3-methyhsoquinohn-5-amine (Description 73) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 396 (M + H)+.
Example 96 N-[3-Methyl-7-(trifluoromethyl)isoquinohn-5-vn-JV-[4- (trifluoromethvDbenzyll urea
Prepared from 3-methyl-7-(trifluoromethyl)isoquinohn-δ-amine (Description 74) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 428 (M + H)+.
Example 97 N-(8-Fluoro-3-methvhsoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzvnurea Prepared from 8-fluoro-3-methyhsoquinohn-δ-amine (Description 76) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 378 (M + H)+.
Example 98
N-(6-Fluoro-3-methyhsoquinohn-5-yl)-JV-[4-(trifl.uoromethyl)benzyl]urea Prepared from 6-fluoro-3-methyhsoquinohn-δ-amine (Description 79) and [4- δ (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 378 (M + H)÷.
Example 99
^(e-Fluoro-S-methvhsoquinohn-δ-vD-JV-^-ftrifluoromethoxy^benzyllurea 10 Prepared from 6-fluoro-3-methyhsoquinohn-δ-amine (Description 79) and [4-
(trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. m/z (ES+) 394 (M + H)+.
Example 100 lδ N- (3-Methylcinnohn- δ - yl) - JV- [4- (trifluoromethoxy)benzyIj urea Prepared from 3-methylcinnolin-δ-amine and
[4- (trifluoromethoxy)benzyl] isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 377 (M + H)+.
20 Example 101
N-(7-Methoxyisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzvnurea
Prepared from 7-methoxyisoquinohn-δ-amine (Description 82) and [4-
(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 376 (M + H)+. 25
Example 102
JV-(1.3-Dimethyhsoquinohn-5-yl)-JV-[4-(trifluoromethyl benzyllurea
Prepared from l,3-dimethyhsoquinohn-5-amine (Description 83) and [4-
(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61.
30 m/z (ES+) 374 (M + H)+.
Example 103
JV-(7-Chloro-3-methyhsoquinohn-5-yl)-JV-[4-(trifl.uoromethv benzvnurea Prepared from 7-chloro-3-methyhsoqτιinohn-δ-amine (Description 86) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 394 (M + H)+.
Example 104
N-(7-Chloroisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzvnurea Prepared from 7-chloroisoquinohn-5-amine (Description 87) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 380 (M + H)+.
Example 105
N-(8-Fluoro-3-methoxyisoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea Prepared from 8-fluoro-3-methoxyisoquinoline-δ-carboxylie acid (Description 88) and 4-(trifluoromethyl)benzylamine according to Description 60. m/z (ES+) 394 (M + H)+.
Example 106 N-(6-Fluoroisoquinohn-5-yl)-JV-r4-(trifluoromethyl)benzyllurea
Prepared from 6-fluoroisoquinohn-δ-amine (Description 89) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. rn/ø (ES+) 364 (M + H)+.
Example 107
JV-(6-Fluoroisoquinohn-δ-yl)-JV-[4-(trifluoromethoxy)benzyl]urea Prepared from 6-fluoroisoquinolin-5-amine (Description 89) and [4- (trifluoromethoxy)benzyl]isocyanate (Description 69) according to Description 61. m/z (ES+) 394 (M + B.)f
Example 108
N-(7-Fluoroisoquinohn-δ-yl)-JV-r4-(trifluoromethyl)benzvnurea
Prepared from 7-fluoroisoquinolin-δ-aιnine (Description 90) and [4-
(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 364 (M + H)+.
Example 109
N-(4-Methyhsoquinohn-5-yl)-JV-[4-(trifluoromethyl)benzyl]urea Prepared from 4-methyhsoquinohn-5-amine (Description 91) and [4- (trifluoromethyl)benzyl]isocyanate (Description 68) according to Description 61. m/z (ES+) 360 (M + H)+.
Example 110
JV-[8-(trifluoromethyl)isoquinohn-δ-vn-JV-[4-(trifl.uoromethyl)benzyllurea
To a solution of 8-(trifluoromethyl)isoquinohn-δ-amine (Description 93; lδO mg, 0.708 mmol) in CDC13 (10 ml) was added [4- (trifluoromethyl)benzyl] isocyanate (Description 58) [0.506M soln in DCM; 1.403 ml, 0.71 mmol) and the resulting mixture heated at reflux overnight. NMR analysis showed a deficit of the [4- (trifluoromethyl)benzyl] isocyanate in comparison to remaining 8- (trifluoromethyl)isoquinolin-5-amine so a further portion of [4- (trifluoromethyl)benzyl]isocyanate [0.606M solution in DCM] (1.403ml ;
0.71mmol) was added and refluxing continued for 2 days. The cooled reaction mixture was evaporated to dryness and purified by column chromatography on silica elution with 1% MeOH in DCM + 0.5% NH4OH. NMR showed the product was the bis acylated urea. This material was dissolved in methanol (5 ml) and K2CO3 (600 mg, 3.6 mmol) added and the mixture stirred at room temperature for 2.5 hours. The mixture was filtered and the residue purified by preparative TLC eluting with 10% MeOH in DCM + 0.5% NH4OH to give the title compound (100 mg, 34%) as a white sohd. m/z (ES+) 414 (M + H)+.
Example 111
JV- [6-(trifluoromethyl)isoquinohn-δ-yll -JV- r4-(trifluoromethyl)benzyllurea To a solution of 6-(trifluoromethyl)isoquinohn-5-amine (Description 98; 100 mg, 0.47 mmol) in anhydrous toluene (5 ml) was added [4-
(trifluoromethyl)benzyl]isocyanate (Description 68) [0.506M soln in DCM] (1.88 ml ; 0.94 mmol) and the mixture heated at reflux overnight. Further [4-
(trifluoromethyl)benzyl]isocyanate [0.606M soln in DCM] (1.88 ml ; 0.94 mmol) was added and heating continued for 4 days. The toluene was removed, the residue dissolved in methanol (10 ml) and a spatula end of potassium carbonate added. The mixture was then heated at reflux for 15 mins. The mixture was
cooled and filtered and the nitrate evaporated. The residue was purified by mass directed HPLC to give the title compound (8 mg, 4%) as a white sohd. m/z (ES+) 414 (M + H)+.
Example 112
N-[7-(trifiuoromethyl)isoquinohn-δ-yll-JV-r4-(trifluoromethyl)benzyl1urea Prepared from 7-(trifluoromethyl)isoquinohn-5-amine (Description 99) and [4- (trifluoromethyl)benzyl]isocyanate (Description 68) according to Description 61. m/z (ES+) 414 (M + H)+.
10
Example 113
N-[7-(trifluoromethyl)isoquinohn-5-yl1-JV-r4-(trifluoromethoxy)benzyl]urea Prepared from 7-(trifluoromethyl)isoquinolin-δ-amine (Description 99) and [4- (trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. lδ m/z (ES+) 414 (M + H)+.
Example 114
N-(6-Fluoro-l-methvhsoquinohn-δ-v -N'-[4-(trifluoromethyl)benzyl1urea Prepared from 6-fluoro-l-methyhsoquinohn-5-amine (Description 103) and [4- 20 (trifluoromethyl)benzyl]isocyanate (description 68) according to the procedure of description 61. m/z (ES+) 378 (M + H)+.
Example 115
N-(l-Cyanoisoqxι ol-in-5-yl -N,-f4-(trifluoroιnethyl)benzyl]urea 25 To a solution of N-(l-cHoroisoquinolin-5-yl)-N-[4-(trifluoromethyl)benzyl]urea
(Example 69) (250 mg, 0.7mmol) in DMF (5 ml) was added zinc cyanide (43 mg,
0.37 mmol) and tetrakis(triphenylphosphine)paUadium (76 mg, 0.07mmol). The reaction was heated at 80°C, under an atmosphere of nitrogen, for 72 hr, with the addition of extra tetrakis(triphenylphosphine)palladium (76 mg, 0.07 mmol) after
30 16 hr. Reaction mixture was quenched with water and extracted with ethyl acetate (3 5 ml), dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using an eluant system of 3% methanol/97% DCM increasing to 5% MeOH/ 95% DCM. RecrystaUisation in ethanol of a small portion of product gave a pure sample of the title compound (50 mg, 65.6%). m/z
35 (ES+) 371, 373 (M + H)+.
Example 116
^^-(Mefl oxycarbony isoquinol-m-S-yll-N^-^faifluoroinethyl^bei-izy^urea Prepared from methyl δ-aminoisoquinohne-1-carboxylate (Description 106) and δ [4-(trifluoromethyl)benzyl]isocyanate (description 68) according to the procedure of description 61. m/z (ES+) 404 (M + H)+.
Example 117
N-Q-Carboxyisoquinolin-S-yh-N'-f^faifluoromethyl^benzyllurea 10 N-[l-(Methoxycarbonyl)isoquinohn-5-yl]-N-[4-(trifluoromethyl)benzyl]urea (Example 116, δδ mg, 0.136 mmol) was dissolved in a mixture of THF (3 ml), methanol (1 ml) and water (1 ml), then hthium hydroxide monohydrate (6 mg, 0.14 mmol) was added. The reaction was stirred at room temperature until aU the ester had been consumed, then the solvents were evaporated and δ% aqueous lδ NaH2PO4 solution (pH 4, δ ml) was added to the residue. After stirring for lδ min. the pale yeUow sohd was coUected by filtration, washed with water (2 ml) and dried under vacuum to give the title compound (39 mg, 73 %). m/z (ES+) 390 (M + H)+.
20 Example 118
N-(l-Aminoisoquinohn-δ-yl)-N'- 4-(trifluoromethyl)benzynurea A mixture of N-(l-carboxyisoquinolin-5-yl)-N'-[4-(trifluoronαethyl)berιzyl]urea (Example 117, 309 mg, 0.794 mmol), diphenylphosphoryl azide (210 μl, 0.975 mmol) and Methyla ine (210 μl, 1.50 mmol) in 1,4-dioxane (25 ml) was heated at 100 °C,
25 under a nitrogen atmosphere for 1.5 h. Water (0.25 ml) was then added and the reaction mixture heated for a further 1 hour. The reaction mixture was then cooled to room temperature, filtered and the filtrate evaporated. The residue was purified using a Bond-Elut SCX ion-exchange cartridge, first eluting non-basic materials with methanol, then eluting the product with 2M methanohc ammonia. The basic fractions
30 were evaporated and further purified by flash column chromatography (eluant 5 % MeOH - 95% dichloromethane increasing to 10% MeOH - 90% dichloromethane). The product was then passed through a second SCX purification to give the title compound (77 mg, 27%). m/z (ES+) 361 (M + H)+.
Example 119
JV- [1- (HvdroxymethvDisoquinolin-δ-yll - JV- r4-(trifluoromethyl)benzvn urea N-[l-(Methoxycarbonyl)isoquinohn-5-yl]-N-[4-(trifluoromethyl)benzyl]urea (Example 116, 70 mg, 0.174 mmol) was suspended in a mixture of THF (5 ml) and toluene (5 ml). Lithium borohydride (50 mg, 2.27 mmol) was added and the reaction mixture heated at 60 °C for 1 hour. The reaction was cooled to room temperature and allowed to stand for 1 week. The crystalline product was coUected by filtration, washed with toluene (2 ml), then triturated with 1:1 THF- dichloromethane (2 ml), triturated again with THF (2 ml) and dried under vacuum to give the title compound (8 mg, 12 %). m/z (ES+) 376 (M + H)+.
Example 120
^^-(MethoxycarbonyDisoquinolin-δ-yll-N'-f^faifluorornethyDbenzy^urea Prepared from methyl 5-aminoisoquinohne-3-carboxylate (Description 107) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 404 (M + H)+.
Example 121
N-(3-Carboxyisoquinolin-5-yl)-N'-[4-(trifluoromethyl)benzyllurea Prepared from N-[3-(methoxycarbonyl)isoquinolin-5-yl]-N'-[4-
(trifluoromethyl)benzyl]urea (Example 120) according to the procedure of Example 117. m/z (ES+) 390 (M + H)+.
Example 122 N-[3-(Dimethylamino isoquinolin-5-yll-JV-[4-(trifluoromethyl)benzyl1urea
Prepared from 3-(dimethylamino)isoquinolin-δ-amine (Description 109) and [4- (trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of description 61. m/z (ES+) 389 (M + H)+.
Example 123
N-r3-(2-Aminoethyl)isoquinohn-5-yll-JV-r4-(trifluoromethyl)benzvnurea To a solution of terf-butyl 2-(5-aminoisoquinohn-3-yl)ethylcarbamate (Description 116; 200 mg, 0.7 mmol) in deuterated chloroform (δ ml) was added [4- (trifluoromethyl)benzyl]isocyanate (0.506M solution in DCM) (Description 58;
1.38 ml, 0.7 mmol), and the resulting mixture heated at reflux overnight. The reaction mixture was cooled and the precipitate removed by filtration, washed with DCM and dried. The sohd was dissolved in methanol (10 ml) and hydrogen chloride gas passed through the mixture for δ mins, after which time the mixture was left standing for 1 hour. The mixture was evaporated and purified using an SCX cartridge - appropriate fractions were evaporated to give the title compound (26 mg, 9%) as a white sohd. m/z (ES+) 389 (M + H)+.
Example 124 ^(δ-Methoxyisoquinohn-δ-yD-JV-^-ftrifluoromethvDbenzy^urea
Prepared from 8-methoxyisoquinohn-δ-amine which was prepared from 8- methoxy-δ-nitroisoquinohne (J. Het. Chem. 37(5), 1293) according to Description 43 and immediately used in reaction with [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 376 (M + H)+.
Example 125 N-Isoquinohn-7-yl-JV-[4-(trifluoromethyl)benzyl]urea
A mixture of isoquinohn-7-yl trifluoromethanesulfonate (Description 117, 1.04 g, 3.7δ mmol), cesium carbonate (1.6 g, 4.88 mmol), benzophenone imine (747 mg, 4.13 mmol), BINAP (100 mg, 0.16 mmol) and paUadium acetate (18 mg, 0.08 mmol) in tetrahydrofuran (lδ ml) was degassed (N2 x 3) then heated at reflux for 18 h. More BINAP (100 mg, 0.16 mmol) and paUadium acetate (18 mg, 0.08 mmol) were added and the reaction heated for a further 24 h. The reaction was then cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with more ethyl acetate (50 ml) and the combined organic layers were evaporated. The residue was taken up in tetrahydrofuran (40 ml) and 2N hydrochloric acid (aq. 10 ml) was added. After 2h, the THF was evaporated, 3N hydrochloric acid (aq. 100 ml) was added and the mi-xture washed with ethyl acetate (2 x 75 ml). The aqueous layer was then basified by addition of 47% aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 50 ml). The combined organic layers were dried (Na2SO4) and evaporated to give crude isoquinohn-7-amine (198 mg) which was reacted directly with [4- (trifluoromethyl)benzyl] isocyanate (Description 58)
according to Description 61 to give the title compound (100 mg, 8%). m/z (ES+) 346 (M + H)+.
Example 126
5 N-JV-Diisoquinohn-δ-ylurea
Prepared from isoquinoline-5-carboxyhc acid and isoquinohn-δ-amine according to Description 60. m/z (ES+) 315 (M + H)+.
Example 127 0 N-Isoquinohn-5-yl-JV-[4-(trifluoromethyl)phenvnurea
Prepared from isoquinohn-5-amine and 4-(trifluoromethyl)phenyl isocyanate according to Description 61. m/z (ES+) 332 (M + H)+.
Example 128 5 N-Isoquinohn-δ-yl-JV-{ 2-(trifluoromethyl)pyrimidin-5-yllmethyl|urea Prepared from isoquinohne-5-carboxyhc acid and 5-(aminomethyl)-2- (trifluoromethyl)pyrimidine (Description 121) according to the procedure of Description 60. m/z (ES+) 348 (M + H)+.
0 Example 129
Ethyl 3-{r(isoquinohn-5-ylamino carbonyllamino}-2-[4-(trifl.uoromethyl)benzyll propanoate
Ethyl 2-cyano-3-[4-(trifluoromethyl)phenyl]prop-2-enoate (136 mg,0.δ mmol), paUadium hydroxide (20 wt% Pd (dry basis on carbon), 20 mg) in ethanol (20 ml) δ containing 2N hydrochloric acid (1 ml) was placed on a Parr apparatus at 3δ psi hydrogen pressure and shaken for 1.5 hours. The reaction mixture was filtered and evaporated to give the corresponding1 amine which was taken up in THF (5 ml). In a separate flask isoquinohn-δ-amine (72mg, O.δmmol) in THF (δ ml) at 0 °C was treated with triphosgene (48 mg, 0.166 mmol) foUowed by triethylamine 0 (140 μL). After 30 minutes, the amine solution was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then filtered and evaporated. Purification by column chromatography using 2.δ%methanol in dichloromethane gave the desired product (49mg). m/z (ES+) 446 (M + H)+.
Example 130
3-{[(isoquinohn-5-ylamino)carbonvnaminol-2-[4-(trifl.uoromethyl)benzvnpropanoic acid Ethyl 3-{[(isoquinohn-δ-ylamino)carbonyl] amino}-2- [4-(trifluoromethyl)benzyl] propanoate (Example 129, 23 mg, 0.05 mmol) in aqueous THF (1:1, 2 ml) was treated with hthium hydroxide (5 mg, 0.1 mmol) and stirred at room temperature for 20 h. The mixture was evaporated then partitioned between 7 % aqueous citric acid and dichloromethane (2:1, 6ml). A precipitate formed which was coUected by filtration and dried azeotropicaUy by adding toluene and evaporating to give the desired compound (8.4 mg). m/z (ES+) 418 (M + H)+.
Example 131
N-Isoquinohn-δ-yl-JV-[4-(morphohn-4-ylmethyl)benzyllurea A solution of isoquinohne-δ-carbonyl azide (Description 126, 60 mg, 0.2δ mmol) in toluene (5 mL) was heated at 76 °C for 1 h. The reaction was cooled to 50 °C and 4-(morphohn-4-ylmethyl)benzylamine (Description 123, 0.31 mmol) was added as a solution in CH2CI2 (1 ml). The precipitated product was coUected by filtration and washed with hexane, then further purified using mass-directed HPLC to give the title compound (2.5 mg, 3%). m/z (ES+) 376 (M + H)+.
Example 132
N-Isoquinohn-5-yl-JV-[2-(2-morpholin-4-ylethoxy)-4-(trifluoromethyl)benzyllurea A solution of isoquinohne-δ-carbonyl azide (Description 126, 43 mg, 0.22 mmol) in toluene (4 mL) was heated at 80 °C for 50 min. The reaction was cooled to 50 °C and 2-(2-morphohn-4-ylethoxy)-4-(trifluoromethyl)benzylamine (Description 125, 66 mg, 0.22 mmol) was added as a solution in toluene (1 ml). The precipitated product was coUected by filtration and washed with dichloromethane to give the title compound (83 mg, 80%). m/z (ES+) 475 (M + H)+.
Claims
A compound of formula (I):
(I) wherein
A, B, D and E are each C or N with the proviso that one or more are N; R1 and R2 are each independently hydrogen, halogen, hydroxy, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, haloCi-ealkyl, hydroxyCι-6alkyl, Ci-βalkoxy, haloCi-ealkoxy, hydroxyCi-ealkoxy, C3-7cycloalkyl, C3-5cycloalkylCι-4alkyl, NR7R8, carboxy, esterified carboxy, Ci-βalkyl substituted with a group selected from NR7R8, carboxy and esterified carboxy, or Ci-βalkoxy substituted with a group selected from NR7R8, carboxy and esterified carboxy; R3 and R4 are each independently hydrogen, Ci-βalkyl, C2-6alkenyl or C2-6alkynyl; R5 and R6 are, at each occurrence, independently hydrogen, Ci-βaUcyl, C2-6alkenyl, C2-6alkynyl, Ci-βalkoxy, Ci-βacyloxy, carboxy, esterified carboxy, CONR7R8, SO2R7, SO2NR7R8, aryl, heteroaryl, heterocyclyl, or Ci-ealkyl substituted with a group selected from hydroxy, Ci-βalkoxy, Ci-βacyloxy, carboxy, esterified carboxy, NR7R8, CONR7R8, SR7, SO2R7, SO2NR7R8, aryl, heteroaryl and heterocyclyl; or R5 and R6 and the carbon atom to which they are attached together form a carbocychc ring of 3 to 6 carbon atoms;
R7 and R8 are, at each occurrence, independently hydrogen, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl or fluoroCi-ealkyl; or R7 and R8 and the nitrogen atom to which they are attached together form a heteroahphatic ring of 4 to 7 ring atoms, optionaUy substituted by one or two groups selected from hydroxy or Cι-4alkoxy, which ring may optionaUy contain as one of the said ring atoms an oxygen or a sulfur atom, a group S(O) or S(O)2, or a second nitrogen atom which wiU be part of a NH or NRa moiety where Ra is Cι-4alkyl optionaUy substituted by hydroxy or Cι-4alkoxy; X is an oxygen or sulfur atom or the group =NCN;
Y is an aryl, heteroaryl, carbocyclyl or fused-carbocyclyl group; and n is either zero or an integer from 1 to 3; or a pharmaceuticaUy acceptable salt, N-oxide or a prodrug thereof.
2. A compound according to claim 1 in which X is O.
3. A compound according to claim 1 or 2 in which R3 and R4 are hydrogen.
4. A compound according to claim 1, 2 or 3 in which B is nitrogen and A, D and E are carbon.
δ. A compound according to any preceding claim in which Y is an aryl group selected from unsubstituted phenyl or naphthyl and phenyl or naphthyl substituted by one or two substituents selected from halogen, Cι-4alkyl, Cι-4alkoxy, haloCι-4alkyl, haloCι-4alkoxy, phenyl, cyano, nitro, pyrazolyl, di(Cι-6alkyl)amino, phenoxy, -OCH2O- and Ci-βalkylcarbonyl; or a heteroaryl group selected from pyridyl, thiazolyl, isoxazolyl, oxadiazolyl and pyrazolyl wherein each heteroaryl group is optionaUy substituted with one or two substituents selected from Cι-4alkyl, Cι-4alkoxy, haloCι-4alkyl, haloCι-4alkoxy, unsubstituted heteroaryl or phenyl which may be substituted by Ci-ealkyl or halogen; or a carbocyclyl group which is a Cs^cycloalkyl radical that is unsubstituted or substituted by a phenyl ring; or a fused-carbocyclyl group which is a C5-7cycloalkyl radical that is fused to a phenyl ring.
6. A compound according to any preceding claim wherein R5 and R6 each independently represent a hydrogen atom or a Cι-4alkyl or phenyl group.
7. A pharmaceutical composition comprising a compound according to any preceding claim or a pharmaceuticaUy acceptable salt or N-oxide thereof.
8. A compound according to any one of claims 1 to 6 or a pharmaceuticaUy acceptable salt or N-oxide thereof for use in a method of treatment of the human or animal body by therapy.
9. Use of a compound according to any one of claims 1 to 6 or a pharmaceuticaUy acceptable salt or N-oxide thereof for use in the manufacture of a medicament for treating diseases and conditions in which pain and/or inflammation predominates.
10. A method of treating a subject suffering from a disease or condition in which pain and/or inflammation predominates which comprises administering to that subject a therapeuticaUy effective amount of a compound according to claim 1 or a pharmaceuticaUy acceptable salt or N-oxide thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0206876 | 2002-03-22 | ||
GBGB0206876.5A GB0206876D0 (en) | 2002-03-22 | 2002-03-22 | Therapeutic agents |
PCT/GB2003/001302 WO2003080578A1 (en) | 2002-03-22 | 2003-03-21 | Heteroaromatic urea derivatives as vr-1 receptor modulators for treating pain |
Publications (1)
Publication Number | Publication Date |
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EP1490340A1 true EP1490340A1 (en) | 2004-12-29 |
Family
ID=9933569
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03710014A Withdrawn EP1490340A1 (en) | 2002-03-22 | 2003-03-21 | Heteroaromatic urea derivatives as vr-1 receptor modulators for treating pain |
Country Status (6)
Country | Link |
---|---|
US (1) | US7285563B2 (en) |
EP (1) | EP1490340A1 (en) |
JP (1) | JP2005526798A (en) |
CA (1) | CA2479150A1 (en) |
GB (1) | GB0206876D0 (en) |
WO (1) | WO2003080578A1 (en) |
Families Citing this family (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7074805B2 (en) | 2002-02-20 | 2006-07-11 | Abbott Laboratories | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
WO2004007459A2 (en) * | 2002-07-12 | 2004-01-22 | Janssen Pharmaceutica N.V. | Naphthol, quinoline and isoquinoline-derivatives as modulators of vanilloid vr1 receptor |
EP2426122A1 (en) * | 2002-10-24 | 2012-03-07 | Merck Patent GmbH | Methylene urea derivative as RAF kinasse inhibitors |
GB0226724D0 (en) | 2002-11-15 | 2002-12-24 | Merck Sharp & Dohme | Therapeutic agents |
AU2003300791A1 (en) * | 2002-12-13 | 2004-07-09 | Neurogen Corporation | Combination therapy for the treatment of pain |
US6933311B2 (en) * | 2003-02-11 | 2005-08-23 | Abbott Laboratories | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
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US7015233B2 (en) | 2003-06-12 | 2006-03-21 | Abbott Laboratories | Fused compounds that inhibit vanilloid subtype 1 (VR1) receptor |
MXPA05013550A (en) * | 2003-06-12 | 2006-04-05 | Abbott Lab | Fused compounds that inhibit vanilloid receptor subtype 1 (vr1) receptor. |
US7615557B2 (en) | 2003-10-01 | 2009-11-10 | Xention Limited | Tetrahydro-naphthalene and urea derivatives |
EP1679296A4 (en) | 2003-10-14 | 2007-12-26 | Ajinomoto Kk | Ether derivative |
JP2007523888A (en) | 2003-11-08 | 2007-08-23 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | Tetrahydro-quinolinyl urea derivatives |
US20060035939A1 (en) * | 2004-07-14 | 2006-02-16 | Japan Tobacco Inc. | 3-Aminobenzamide compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity |
RU2392278C2 (en) * | 2004-07-15 | 2010-06-20 | Джапан Тобакко Инк. | Condensed benzamide derivative and inhibitor of vanilloid receptor type 1 activity (vri) |
KR20060087386A (en) | 2005-01-28 | 2006-08-02 | 주식회사 대웅제약 | Novel benzoimidazole derivatives and a pharmaceutical composition comprising the same |
US7700595B2 (en) | 2005-03-01 | 2010-04-20 | Wyeth Llc | Cinnoline compounds |
US7297700B2 (en) | 2005-03-24 | 2007-11-20 | Renovis, Inc. | Bicycloheteroaryl compounds as P2X7 modulators and uses thereof |
DE102005023943A1 (en) | 2005-05-20 | 2006-11-23 | Grünenthal GmbH | Pentafluorosulfanyl-substituted compound and its use for the preparation of medicaments |
ES2580108T3 (en) | 2005-07-11 | 2016-08-19 | Aerie Pharmaceuticals, Inc | Isoquinoline compounds |
US7842703B2 (en) | 2005-10-07 | 2010-11-30 | Glenmark Pharmaceuticals S.A. | Substituted benzofused derivatives and their use as vanilloid receptor ligands |
DE102005059479A1 (en) | 2005-12-13 | 2007-06-14 | Merck Patent Gmbh | hydroxyquinoline |
US7906508B2 (en) * | 2005-12-28 | 2011-03-15 | Japan Tobacco Inc. | 3,4-dihydrobenzoxazine compounds and inhibitors of vanilloid receptor subtype 1 (VRI) activity |
WO2007074916A1 (en) | 2005-12-28 | 2007-07-05 | Japan Tobacco Inc. | 3,4-dihydrobenzoxazine compound and inhibitor of vanilloid receptor type 1 (vr1) activity |
WO2007087441A2 (en) * | 2006-01-25 | 2007-08-02 | Synta Pharmaceuticals Corp. | Substituted aromatic compounds for inflammation and immune-related uses |
MX2008010671A (en) * | 2006-02-21 | 2008-10-01 | Amgen Inc | Cinnoline derivatives as phosphodiesterase 10 inhibitors. |
AU2007221049A1 (en) * | 2006-02-28 | 2007-09-07 | Amgen Inc. | Cinnoline and quinazoline derivates as phosphodiesterase 10 inhibitors |
MX2008011257A (en) * | 2006-03-08 | 2008-09-25 | Amgen Inc | Quinoline and isoquinoline derivatives as phosphodiesterase 10 inhibitors. |
TWI464148B (en) | 2006-03-16 | 2014-12-11 | Evotec Us Inc | Bicycloheteroaryl compounds as p2x7 modulators and uses thereof |
TW200824687A (en) | 2006-08-25 | 2008-06-16 | Abbott Lab | Compounds that inhibit TRPV1 and uses thereof |
WO2008032204A1 (en) | 2006-09-15 | 2008-03-20 | Pfizer Japan Inc. | Substituted pyridylmethyl bicyclocarboxyamide compounds |
CA2664335C (en) | 2006-09-20 | 2014-12-02 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
US8158650B2 (en) | 2006-10-23 | 2012-04-17 | Pfizer Inc. | Substituted phenylmethyl bicyclocarboxyamide compounds |
WO2008057300A2 (en) * | 2006-10-27 | 2008-05-15 | Redpoint Bio Corporation | Trpvi antagonists and uses thereof |
WO2008059339A2 (en) * | 2006-11-13 | 2008-05-22 | Glenmark Pharmaceuticals S.A. | Isoquinoline derivatives as vanilloid receptor modulators |
WO2008059370A2 (en) | 2006-11-17 | 2008-05-22 | Pfizer Japan Inc. | Substituted bicyclocarboxyamide compounds |
CN101563318A (en) | 2006-12-20 | 2009-10-21 | 艾博特公司 | N- (5, 6, 7, 8-tetrahydronaphthalen-1-yl) urea derivatives and related compounds as trpv1 vanilloid receptor antagonists for the treatment of pain |
GB0625594D0 (en) * | 2006-12-21 | 2007-01-31 | Smithkline Beecham Corp | Compounds |
US8455513B2 (en) | 2007-01-10 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
CA2680275C (en) | 2007-03-09 | 2016-08-23 | Renovis, Inc. | Bicycloheteroaryl compounds as p2x7 modulators and uses thereof |
DE102007018149A1 (en) | 2007-04-16 | 2008-10-23 | Grünenthal GmbH | Substituted compound for producing pharmaceuticals for treating or prophylaxis of pain, nerve injuries, respiratory disorder, has general formulae |
JP2010523727A (en) * | 2007-04-16 | 2010-07-15 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Vanilloid receptor ligands and their use in the manufacture of medicaments |
WO2009035951A2 (en) * | 2007-09-11 | 2009-03-19 | Arete Therapeutics, Inc. | Soluble epoxide hydrolase inhibitors |
US8455514B2 (en) | 2008-01-17 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-and 7-amino isoquinoline compounds and methods for making and using the same |
CA2719018A1 (en) | 2008-03-20 | 2009-09-24 | Abbott Laboratories | Methods for making central nervous system agents that are trpv1 antagonists |
CN101983197B (en) | 2008-04-18 | 2015-04-22 | 大熊制药株式会社 | A novel benzoxazine benzimidazole derivative, a pharmaceutical composition comprising the same, and a use thereof |
EP2116618A1 (en) | 2008-05-09 | 2009-11-11 | Agency for Science, Technology And Research | Diagnosis and treatment of Kawasaki disease |
US8450344B2 (en) | 2008-07-25 | 2013-05-28 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
US8604053B2 (en) * | 2008-10-17 | 2013-12-10 | Abbvie Inc. | TRPV1 antagonists |
WO2010057101A2 (en) * | 2008-11-17 | 2010-05-20 | Schering Corporation | Compounds useful as hiv blockers |
EP3354643B1 (en) | 2009-05-01 | 2020-10-28 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
AU2010244684B2 (en) * | 2009-05-07 | 2014-07-03 | Grunenthal Gmbh | Substituted aromatic carboxamide and urea derivatives as vanilloid receptor ligands |
JP5745505B2 (en) * | 2009-05-07 | 2015-07-08 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Substituted phenylureas and substituted phenylamides as vanilloid receptor ligands |
US8946204B2 (en) | 2009-05-07 | 2015-02-03 | Gruenenthal Gmbh | Substituted phenylureas and phenylamides as vanilloid receptor ligands |
CN102448937A (en) * | 2009-05-29 | 2012-05-09 | 拉夸里亚创药株式会社 | Aryl Substituted Carboxamide Derivatives As Calcium Or Sodium Channel Blockers |
SG10201406178WA (en) * | 2009-09-29 | 2014-11-27 | Allergan Inc | Condensed ring pyridine compounds as subtype-selective modulators of sphingosine-1-phosphate-2 (s1p2) receptors |
EP2377850A1 (en) * | 2010-03-30 | 2011-10-19 | Pharmeste S.r.l. | TRPV1 vanilloid receptor antagonists with a bicyclic portion |
US20130096119A1 (en) | 2010-03-31 | 2013-04-18 | Daniel Bur | Isoquinolin-3-Ylurea Derivatives |
KR101293384B1 (en) | 2010-10-13 | 2013-08-05 | 주식회사 대웅제약 | Novel pyridyl benzoxazine derivatives, pharmaceutical composition comprising the same, and use thereof |
UY33966A (en) * | 2011-03-25 | 2012-10-31 | Abbott Lab | VANILLOID POTENTIAL TRANSITORY RECEIVER ANTAGONISTS 1 (TRPV1) |
AR088729A1 (en) | 2011-03-29 | 2014-07-02 | Actelion Pharmaceuticals Ltd | DERIVATIVES OF 3-UREIDOISOQUINOLIN-8-ILO AND A PHARMACEUTICAL COMPOSITION |
US9181261B2 (en) * | 2012-05-22 | 2015-11-10 | Merck Sharp & Dohme Corp. | TrkA kinase inhibitors, compositions and methods thereof |
EP3461484B9 (en) | 2013-03-15 | 2021-06-09 | Aerie Pharmaceuticals, Inc. | Dimesylate salts of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl, their combinations with prostaglandins and the use thereof in the treatment of ocular disorders |
CN104016914B (en) * | 2014-05-27 | 2016-03-30 | 苏州科技学院 | A kind of preparation method of amide compound |
TW201607927A (en) * | 2014-08-28 | 2016-03-01 | 愛沃特股份有限公司 | Method for producing isoquinolines |
WO2017086941A1 (en) | 2015-11-17 | 2017-05-26 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
CN105906564B (en) * | 2016-05-05 | 2018-11-30 | 海南省药物研究所 | Compound, preparation method and its usage |
MX2019002396A (en) | 2016-08-31 | 2019-07-08 | Aerie Pharmaceuticals Inc | Ophthalmic compositions. |
US9840468B1 (en) * | 2016-12-30 | 2017-12-12 | Aerie Pharmaceuticals, Inc. | Methods for the preparation of 6-aminoisoquinoline |
EP3609871A4 (en) | 2017-03-31 | 2021-01-06 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
US10696638B2 (en) | 2017-12-26 | 2020-06-30 | Industrial Technology Research Institute | Compounds for inhibiting AGC kinase and pharmaceutical compositions comprising the same |
AU2019337703B2 (en) | 2018-09-14 | 2023-02-02 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
CN109836423B (en) * | 2019-04-03 | 2020-04-10 | 黑龙江中医药大学 | Novel compound for preventing or treating pulmonary fibrosis diseases, preparation method and application thereof |
CN112457245B (en) * | 2020-11-11 | 2022-11-22 | 苏州康润医药有限公司 | Synthesis method of 7- (trifluoromethyl) isoquinoline-5-amine |
DE102022104759A1 (en) | 2022-02-28 | 2023-08-31 | SCi Kontor GmbH | Co-crystal screening method, in particular for the production of co-crystals |
WO2024121048A1 (en) * | 2022-12-05 | 2024-06-13 | Angelini Pharma S.P.A. | Urea compounds as activators of potassium channels kv7.2/7.3 useful in the treatment of cns and pns disorders |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003070247A1 (en) * | 2002-02-20 | 2003-08-28 | Abbott Laboratories | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (vr1) receptor |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE583207C (en) * | 1931-08-18 | 1933-08-30 | I G Farbenindustrie Akt Ges | Process for the preparation of urea clusters of the heterocyclic series with quaternary ring nitrogen |
DE1157626B (en) * | 1959-06-27 | 1963-11-21 | Hoechst Ag | Process for the preparation of N-p-alkoxy-phenyl-N'-quinolylthioureas with tuberculostatic properties |
GB1472766A (en) * | 1974-11-07 | 1977-05-04 | Ici Ltd | Hydroxycinnoline derivatives processes for their preparation and their use in pharmaceutical compositions |
DE2502588A1 (en) * | 1975-01-23 | 1976-07-29 | Troponwerke Dinklage & Co | Coronary dilating 7-amino-2-quinolone derivs - prepd. e.g. by reacting 1,3-phenylenediamines with aminoalkyl-substd. acetoacetates |
US5508288A (en) * | 1992-03-12 | 1996-04-16 | Smithkline Beecham, P.L.C. | Indole derivatives as 5HT1C antagonists |
JPH07503737A (en) * | 1992-05-28 | 1995-04-20 | フアイザー・インコーポレイテツド | Acyl-coenzyme A: Novel N-aryl and N-heteroaryl urea derivatives as inhibitors of cholesterol acyltransferase (ACAT) |
WO1994014801A1 (en) | 1992-12-29 | 1994-07-07 | Smithkline Beecham Plc | Heterocyclic urea derivatives as 5ht2c and 5ht2b antagonists |
GB9823873D0 (en) | 1998-10-30 | 1998-12-30 | Pharmacia & Upjohn Spa | 2-ureido-thiazole derivatives,process for their preparation,and their use as antitumour agents |
KR20030024799A (en) * | 2000-07-20 | 2003-03-26 | 뉴로젠 코포레이션 | Capsaicin receptor ligands |
EP1414788A1 (en) | 2001-07-31 | 2004-05-06 | Bayer HealthCare AG | Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists |
US20030158188A1 (en) * | 2002-02-20 | 2003-08-21 | Chih-Hung Lee | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
US7074805B2 (en) * | 2002-02-20 | 2006-07-11 | Abbott Laboratories | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
-
2002
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- 2003-03-21 WO PCT/GB2003/001302 patent/WO2003080578A1/en active Application Filing
- 2003-03-21 JP JP2003578333A patent/JP2005526798A/en active Pending
- 2003-03-21 EP EP03710014A patent/EP1490340A1/en not_active Withdrawn
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003070247A1 (en) * | 2002-02-20 | 2003-08-28 | Abbott Laboratories | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (vr1) receptor |
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US20050107388A1 (en) | 2005-05-19 |
CA2479150A1 (en) | 2003-10-02 |
AU2003214442A1 (en) | 2003-10-08 |
GB0206876D0 (en) | 2002-05-01 |
JP2005526798A (en) | 2005-09-08 |
US7285563B2 (en) | 2007-10-23 |
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